Revista da Associação Médica Brasileira

Transcription

Volume 60
Número 5
Setembro/Outubro 2014
ISSN 0104-4230
ISSN 1806-9282 (On-line)
Revista da Associação Médica Brasileira
SectionS
Editorial
Fifteen minutes
395
a c c r E d i tat i o n
Update on angle-closure glaucoma:
treatment
398
Update on late-onset hypogonadism (LOH)
or ADAM: diagnosis
399
Identification of hepatitis B virus genotypes
in the state of São Paulo
424
Reeducation of pelvic floor muscles in
volleyball athletes
428
Expansion of morbidity: trends in healthy life
expectancy of the elderly population
434
Pregnancy-induced hypertension syndrome
and cardiovascular risk
442
Prenatal diagnosis of congenital rubella
infection in São Paulo
451
Dietary patterns are associated with general
and central obesity in elderly living in a
Brazilian city
457
Risk factors for episiotomy: a case-control
study
465
Spontaneous rupture of renal pelvis secondary
to ureteral obstruction by urothelial tumor
415
Microbiologic profile of hospitalized
healthcare workers
473
at
Investigation of urinary abnormalities and
risk factors for kidney disease in the World
Kidney Day campaigns in Northeast Brazil
479
GuidElinEs
in focus
Degenerative spondylolisthesis: surgical
treatment
400
Late-onset hypogonadism or ADAM:
treatment
404
i m aG E
in mEdicinE
bEdsidE
Stress in nurses in Intensive Care Units
418
ArticleS
How to evaluate quality of life in overweight
and obese women during climacterium?
484
oriGinal
rEviEw
articlEs
Spatial distribution of C-sections within the
state of São Paulo
419
articlE
Waldenström’s macroglobulinemia –
a review
www.ramb.org.br
490
REVISTA DA ASSOCIAÇÃO MÉDICA BRASILEIRA
Journal of the Brazilian Medical Association
www.ramb.org.br
Editorial Board for 2011-2014
Editor-in-chief
Antônio Jorge Salomão
Co-editors
José Maria Soares Jr.
Wanderley M. Bernardo
Administrative Co-editor
Paula Jereissati
Associated Editors
Albert Bousso
Anna Andrei
Auro Del Giglio
Daniel Deheinzelin
Edna Frasson de S. Montero
Eduardo F. Borba
Elias Jirjoss Ilias
Isabela Giuliano
José Maria Soares Jr.
José Mendes Aldrighi
International Editors
Andre D’Avila
Dimas Ikeoka
Edmundo M. Ferraz
Eduardo de Souza
Eduardo Weltman
Emmanuel A. Burdmann
Gilberto Schwartsmann
Hillegonda M. Durithl Novaes
Ivan Ceconello
José Eduardo de Siqueira
Júlio Coelho
Luana Carandina
Luís Bahamondes
Luís Paulo Kowalski
Marcelo Gurgel C. da Silva
Márcia R. Pinho Makdisse
Marco A. Borges Lopes
Marcos Roberto Tavares
Maria de Lourdes Brizot
Maurício Abrão
Milton A. Martins
Nilton Hideto Takiuti
Paulo A. Carvalho Fortes
Paulo Veiga Jardim
Pedro Luis Squilacci Leme
Pedro Paulo Pereira
Pedro Puech Leão
Raymundo S. Azevedo
Roberto Eduardo Bittar
Rodrigo Ruano
Lucia Pellanda
Nilson Roberto de Melo
Paulo Caramelli
Paulo Kassab
Rossana Pulcineli V. Francisco
Seizo Miyadahira
Werther Bruno W. de Carvalho
Frida Leonetti
Geltrude Mingrone
Giuseppe Barbaro
Marcelo Marotti
Ruy Jorge Cruz Junior
Walter Ageno
Junior Editor
Gabriel Liguori
Advisory Board
Alexandre Biasi Cavalcanti
Alvaro Atalah
Álvaro Petracco
Angelita Habr Gama
Anoi Castro Cordeiro
Antonio José Gonçalves
Carlos A. Cardim de Oliveira
Carlos Alberto Malheiros
Claudio Cohen
Cristina Muccioli
Davi Rumel
Décio Mion
Délcio Matos
Durval Damiani
Rogério Souza
Rolf Gemperli
Rosana P. V. Francisco
Roseane Mattar
Sérgio Nishioka
Sonia Mansoldo Dainesi
Valdir Golin
Victor Bunduki
Volnei Garrafa
Wagner Weidebach
Brazilian Medical Association – Management board – years 2014-2017
President
Petrônio Andrade Gomes
Directors
Florentino de Araújo
Cardoso Filho
José Luiz Weffort
Giovanni Guido Cerri
(Scientific)
1st Vice-president
Jurandir Marcondes
Eleuses Vieira de Paiva
Ribas Filho
2nd Vice-president
Aguinel José Bastian Junior
Lincoln Lopes Ferreira
Eduardo da Silva Vaz
General Secretary
Vice-presidents
Antônio Jorge Salomão
Lairson Vilar Rabelo
1st Secretary
Eduardo Francisco
de Assis Braga
Aldemir Humberto Soares
Cléa Nazaré Carneiro Bichara
Salustiano José Alves
de Moura Junior
Álvaro Roberto Barros Costa
1st Treasurer
José Luiz Bonamigo Filho
2nd Treasurer
Miguel Roberto Jorge
Antonio Carlos Vieira Lopes
(DAP)
Jane Maria Cordeiro Lemos
(Cultural)
Emilio Cesar Zilli
(Professional Defense)
Nívio Lemos Moreira Junior
(International Relations)
Rafael Klee de Vasconcelos
(Medical Economics)
Jorge Carlos Machado Curi
(Public Health)
Diogo Leite Sampaio
(Communications)
Edmund Chada Baracat
(Academic)
Antonio Carlos Weston
(Member’s Helpline)
Márcio Silva Fortini
(Patient Protects)
Carmelo Silveira Carneiro
Leão Filho Marketing)
José Luiz Dantas Mestrinho
(Parliamentary Affairs)
Brasilian Medical Association
Address: Rua São Carlos do Pinhal, 324
Bela Vista – São Paulo
Postal Code: 01333-903
Phone: (11) 3178-6800
Editor-in-Chief: Antônio Jorge Salomão
Head Writter: César Teixeira
e-mail: [email protected]
website: www.ramb.org.br
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Summary
Sections
Editorial
Fifteen minutes
Wanderley Bernardo, José Maria Jr., Antônio Salomão, Edmund Baracat�� 395
Accreditation
Update on angle-closure glaucoma: treatment
Bernardo WM, Prata TS, Kanadani FN, Simões R�� 398
Update on late-onset hypogonadism (loh) or adam: diagnosis
Bernardo WM, Martits AM, Costa EMF, Nardi AC, Nardozza Jr. A, Faria G, Facio Jr. FN�� 399
guidelines in focus
Degenerative spondylolisthesis: surgical treatment
Ricardo V. Botelho, Noel O. Foni, Alberto O. Gotfryd, Carlos Fernando P.S. Herrero, Jefferson Daniel, Robert Meves, Marcelo Luis Mudo,
Ricardo S. Simões, Sérgio Zylbersztejn, Wanderley M. Bernardo�� 400
Late-onset hypogonadism or ADAM: treatment
Martits AM, Costa EMF, Nardi AC, Nardozza Jr. A, Facio Jr. FN, Faria G, Bernardo WM�� 404
Image in medicine
Spontaneous rupture of renal pelvis secondary to ureteral
obstruction by urothelial tumor
Daniel Alvarenga Fernandes, Ana Laura Gatti Palma, Ricardo Yoshio Zanetti Kido, Ricardo Hoelz de Oliveira Barros, Daniel Lahan Martins, Thiago José Penachim, Nelson Marcio Gomes Caserta.�� 415
at bedside
Rosemeire de Jesus Ferreira Leitão, Janayna Thainá Rabelato, Wanderley Marques Bernardo�� 418
Original Articles
Spatial distribution of C-sections within the state of São Paulo
Stephani Felício da Silva Campi, Luiz Fernando C. Nascimento�� 419
Identification of hepatitis B virus genotypes in the state of São Paulo
Ana Paula de Torres Santos, José Eduardo Levi, Marcílio Figueiredo Lemos, Samira Julien Calux, Isabel Takano Oba, Regina Célia Moreira �� 424
Reeducation of pelvic floor muscles in volleyball athletes
Silvia Ferreira, Margarida Ferreira, Alice Carvalhais, Paula Clara Santos, Paula Rocha, Gabriela Brochado�� 428
Expansion of morbidity: trends in healthy life expectancy of the elderly population
Alessandro Gonçalves Campolina, Fernando Adami, Jair Licio Ferreira Santos, Maria Lucia Lebrão �� 434
Pregnancy-induced hypertension syndrome and cardiovascular risk
Ana Ciléia Pinto Teixeira Henriques, Júlio César Garcia de Alencar, Lívia Rocha de Miranda Pinto, Rosa Maria Salani Mota,
Raimunda Hermelinda Maia Macena, Helvécio Neves Feitosa, Francisco Herlânio Costa Carvalho �� 442
Prenatal diagnosis of congenital rubella infection in São Paulo
Suely Pires Curti, Cristina Adelaide Figueiredo, Maria Isabel de Oliveira, Joelma Queiroz Andrade, Marcelo Zugaib , Denise Araújo Lapa Pedreira, Edison Luiz Durigon��451
Dietary patterns are associated with general and central obesity in elderly
living in a Brazilian city
Priscila Lucelia Moreira, Jose Eduardo Corrente, Paulo Jose Fortes Villas Boas, Ana Lucia Anjos Ferreira �� 457
Risk factors for episiotomy: a case-control study
Giordana Campos Braga, Suelem Taís Pereira Clementino, Patrícia Ferreira Neves da Luz, Adriana Scavuzzi, Carlos Noronha Neto, Melania Maria Ramos Amorim�� 465
Microbiologic profile of hospitalized healthcare workers
Rafael Barberena Moraes, Andréia Della Giustina, Eliana Madalena Vicentini Farenzena, Laura de Mattos Milman, Renata Sehbe Fedrizzi�� 473
Investigation of urinary abnormalities and risk factors for kidney disease
in the World Kidney Day campaigns in Northeast Brazil
Sônia M.H.A. Araújo, Maria Zenaide D. Ribeiro, Rafael S. A. Lima, Geraldo B. Silva Junior, Camilla N. Jacinto, Moises Francisco da Cruz Neto, Valdenor N. Feitosa Junior,
Marília M. V. Girão, Elizabeth F. Daher�� 479
How to evaluate quality of life in overweight and obese women during climacterium?
Livia Oliveira Munhoz, Isabel Cristina Esposito Sorpreso, Maria Cristina Caceres Nogueira, Ricardo dos Santos Simões, José Maria Soares Junior, Edmund Chada Baracat�� 484
Review Article
Waldenström’s macroglobulinemia – a review
Susana Coimbra, Rafael Neves, Margarida Lima, Luís Belo, Alice Santos-Silva�� 490
Editorial
Fifteen minutes
Fifteen minutes
Quinze minutos
Wanderley Bernardo, José Maria Jr., Antônio Salomão, Edmund Baracat
http://dx.doi.org/10.1590/1806-9282.60.05 .001
Describing the importance of obesity today,
and the lack of strategies for proper management, can take fifteen minutes of reading, but the problem must involve much
more time of your attention, as well as guidance to your patients.
Epidemic and rising rates of obesity in many parts of the
world are leading to increased suffering and economic
stress. Despite decades of research on the causes of the
obesity pandemic, which does not seem close to a solution, there is still no clear understanding of the nature of
the problem. This limits creativity and suffocates expansive thinking, which could advance in the field of prevention and treatment, as well as in the scope of the complications of obesity. Shared decision-making and the
redirecting of policies could remove barriers that prevent
us from moving forward to solve an urgent public health
issue of the beginning of this century1.2.
Overweight and obesity reflect a gain of excess body
fat, including visceral fat, which is a result of initially imperceptible cumulative effects of everyday eating, hourly,
with no proper physical activity, creating a surplus of calories consumed in relation to those expended. Excess
weight gain, gradual and unintended, is accompanied by
the difficulty of reversing the picture and can become permanent. Even if all currently obese patients were treated
effectively in the absence of adequate preventive efforts,
there would still be continued growth in the number of
obese people. Many multifaceted interventions to prevent obesity seek to influence the balance of calories, focusing on energy consumption, or energy expenditure.
While obesity is a priority from an epidemiological and
public health perspective, it becomes even more important as it influences other aspects of society. Substantial
direct and indirect costs include discrimination, economic deprivation, loss of productivity and disability. Thus,
state and local governments end up diverting resources
for prevention and treatment. The country’s health system is burdened with the comorbidities of obesity, such
as type 2 diabetes, hypertension, cardiovascular diseases,
osteoarthritis and cancer. It is estimated that the annual
burden of obesity is almost 10% of all medical spending3.
There are programs of shared decision-making that offer
surgical treatment modalities for weight loss, including:
Rev Assoc Med Bras 2014; 60(5):395-397
Roux-en-Y gastric bypass, laparoscopic adjustable gastric
banding and laparoscopic sleeve gastrectomy. Patients attend seminars where they are instructed on the differences
in outcomes, follow-up and complications of each procedure. The main information presented at the seminar include:
1. Greater weight loss with Roux-en-Y and sleeve gastrectomy
compared to the use of a gastric band; 2. The gastric band
requires the highest number of post-operative visits (monthly in the first year); 3. The Roux-en-Y and the sleeve gastrectomy have a higher rate of life-threatening complications than the gastric band (fistula); 4. The gastric band has
highest number of delayed complications related to the device (erosion, migration); 5. The Roux-en-Y has the highest
rate of diabetes remission; and 6. There is a lack of data on
five-year follow-up of weight loss after sleeve gastrectomy.
Fifty-eight percent of patients chose “weight loss” as the
most important result, and 65% chose “fistula” as the most
worrisome complication. A subgroup analysis including patients with diabetes showed that 58% chose “curing diabetes” as the most important result. Nineteen percent of patients were unsure about which procedure they wanted, or
changed their decision after consultation with the surgeon3.
The choice for bariatric surgery is not easy,
and shared decision-making in the management of obesity should address both the medical and surgical treatment, and prevention, requiring more than fifteen minutes.
In decision-making, patients can choose to be more passive.
That is because they do not know how to feel when they are
more active in decisions. Or, they may fear abandonment or
being labeled “difficult if they seem to defy the doctor’s authority. They may find it difficult to tolerate the doubt, being satisfied with the first solution, less than ideal, but available. In turn, physicians may assume that the patient made
the decision based on correct information and appropriate
assumptions, especially if the professional opinion is naturally favored. It is generally accepted that whenever patients
are well-informed, they can make the best decisions. Patients
often want more information than expected. Sometimes,
however, the more information is presented, the worse is the
understanding of patients. Patients and physicians need to
consider the right amount. In addition, the number and types of suitable options (not all possible options at once) and
395
Wanderley Bernardo, José Maria Jr., Antônio Salomão, Edmund Baracat
the right time to accommodate the limits of individual and
shared cognitive processing. Physicians should be alert to
the potential of hierarchical relationships that can promote coercion or silence the voice of the patient, and regularly
check for understanding. They should also be aware of the
indirect signs of emotional distress and demonstrate reliability and transparency, actively soliciting the patient’s questions and concerns. Self-knowledge, self-monitoring, honesty and the willingness to challenge one’s own assumptions
are key qualities, which, when cultivated by the physician,
will help him/her distinguish his/her participation in increasing autonomy at the expense of well-meaning, but mistaken, imposition of values4.
Proper patient care requires dialogue with
regard to options and decisions, which is
not accomplished in 15 minutes.
• Talking about choices. How to get patients to understand that there are reasonable options? The components of
this stage are: a) Step one – Summarize and say: “Now that
we have identified the problem, it’s time to think about what
to do next”; b) Offer choices - Please note that patients often misinterpret the presentation of choices and think the
doctor is either incompetent or uninformed, or both. Reduce this risk by saying: “There is good information about how
these treatment options differ, and I would like to discuss
this with you”; c) Justify the choice - Emphasize: 1) The importance of respecting individual preferences; 2) The role of
uncertainty. Customize preferences: explain that different issues are more important to some people than to others,
which should be easily understood. Say: “Treatments have
different consequences. Some will be more important to
you than to others.” Uncertainty: Patients often are unaware
of the extent of uncertainty in medicine, how evidence can
be weak and the results, unpredictable at the individual level. Say: “Treatments are not always effective, and the chances of suffering side effects vary.” d) Check the patient’s reaction – The choice among options can be confusing: some
patients may express concern. Suggested phrases: “Let’s continue” or “Should I tell you about the options”? e) Postpone the end of the conversation – Some patients react asking
doctors: “Tell me what to do.” Postpone the end in case this
occurs, assuring your patient that you are willing to support
his/her decision-making process. Say: “I’m happy to share
my opinions and help you reach a good decision. But before I do that, can I describe the options in more detail so that
you understand what is at stake?5
• Talking about the options: a) Check their knowledge
- Even well-informed patients may be only partially awa-
re of the options, and the harms and benefits associated
with the procedures, or they may be misinformed. Evaluate with the question: “What have you heard or read
about the treatment of obesity?”; b) Write the options Make a clear list of alternatives, as this offers good structure. Say: “Let me list the options before we go into more
detail”. If this is the case, add the option “wait watching”
or use positive terms such as “active monitoring”; c) Describe the options (in practical terms) - Generate dialogue
and explore preferences. If there are two medical treatments, says: “Both options are similar and involve taking
medication regularly.” Point out when there are clear differences (surgery or medication), situations in which it is
possible to postpone, or those in which decisions are reversible. Say: “These options have different implications
for you in relation to others, and so I want to describe ...”.
Harm and benefits - Being clear about the pros and cons
of the different options is crucial in shared decision-making. Learn effective communication about risk, effects
of the process, importance of providing data on absolute risk, as well as in relative terms; d) Support the patient’s
decision – Synthetic tools make the options visible and
can save time. Some are sufficiently concise to use in clinical visits. Examples: cards related to the subject, decision charts and option tables. Shared decision may need
more than a medical visit. More extensive tools for patient decision support can play a crucial role. Say: “These tools are designed to help you understand the options
in more detail. Use them and come back so that I can answer your questions.” e) Summarize - List the options again
and assess understanding, asking reformulations5.
• Talking about the decision: a) Focus on preferences Guide the patient to express them. Suggested phrases:
“What, from your point of view, is more important to you?”
b) Inducing a preference - Be prepared to provide additional time or willing to guide the patient if he/she indicates that this is his/her wish; c) Move to a decision - Try
to verify the need to postpone the decision or take it. Suggested phrases: “Are you ready to decide?” / “Do you want
more time?” / “Do you have any other questions?” / “Is
there anything else that we need to discuss?” d) Review
the offer – Reminding the patient, whenever possible, that
decisions can be reviewed is a good way to end the conversation5.
Briefly, patients must decide not only through a theoretical exercise, but considering the context that preserves the expression of their autonomy, in which there must
be: clarity on where the care is provided; about the treatment process or outcome to achieve a particular health
396Rev Assoc Med Bras 2014; 60(5):395-397
Fifteen minutes
status; adequate information regarding their preferences;
perceived credibility of the information source; clarity in
the language used to describe options; attention to different attributes of a decision such as benefits and harms;
number of options available; valuing of previous experiences in similar situations; affection; description of the
effects in the order in which they occur; analysis of reliable opinions of others; perceived social norms; and media influence6.
Modalities that lead to rapid, invasive and irreversible solutions used in the treatment of obesity, which grow
exceeding their applications, occupy the space of absence or failure of preventive measures and medical treatment.
Reading this walkthrough of shared decision-making
can be done in just fifteen minutes. However, in order to
care for patients who suffer, and health systems that do
not know how to preserve them, medicine is in urgent
need of much more than fifteen minutes of dedication.
The consequences of a poor decision can last more than
fifteen minutes, hours, days, months, years or decades.
References
1. Hebert JR, Allison DB, Archer E, Lavie CJ, Blair SN. Scientific decision
making, policy decisions, and the obesity pandemic. Mayo Clin Proc 2013;
88: 593-604.
2. Institute of Medicine (US) Committee on an Evidence Framework for Obesity
Prevention Decision Making; Kumanyika SK, Parker L, Sim LJ, editors.
Bridging theEvidence Gap in Obesity Prevention: A Framework to Inform
Decision Making.Washington (DC): National Academies Press (US); 2010.
3. Weinstein AL, Marascalchi BJ, Spiegel MA, Saunders JK, Fagerlin A, Parikh
M. Patient Preferences and Bariatric Surgery Procedure Selection; the Need
for Shared Decision-Making. Obes Surg 2014.
4. Epstein RM. Whole mind and shared mind in clinical decision-making.
Patient Educ Couns 2013; 90: 200-6.
5. Elwyn G, Frosch D, Thomson R, Joseph-Williams N, Lloyd A, Kinnersley P,
et al. Shared decision making: a model for clinical practice. J Gen Intern
Med 2012; 27:1361-7.
6. Epstein RM, Gramling RE. What is shared in shared decision making?
Complex decisions when the evidence is unclear. Med Care Res Rev 2013;
70 (1 Suppl): 94S-112S.
397
Accreditation
Felipe-Silva A et al.
Update on angle-closure glaucoma: treatment
Atualização em glaucoma de ângulo fechado: tratamento
Bernardo WM, Prata TS, Kanadani FN, Simões R
http://dx.doi.org/10.1590/1806-9282.60.05.002
1. On prophylactic laser iridotomy, in the contralateral eye, in a patient with acute primary angle closure in one eye, we can affirm that:
a.It can prevent similar episodes in many cases.
b.There is no increase in intraocular pressure (IOP) in
treated cases.
c. Cases with higher IOP have less chances of requiring
additional treatment.
d.In such cases, surgical iridectomy should be preferred
over laser iridotomy.
2. The differences between prophylactic laser iridotomy (PLI) and prophylactic surgical iridectomy
include:
a.PLI is more effective.
b.PLI costs less.
c. The surgical procedure is safer.
d.The surgical procedure is more effective.
3. It is not a complication of PLI:
a.Acute IOP rise.
b.Anterior uveitis.
c. Clinical improvement of cataract.
d.Corneal decompensation.
4. Which anatomic situation of the camerular sinus is
an indication for prophylactic laser iridotomy?
a.All cases of suspected primary angle closure.
b.All cases diagnosed as primary angle closure.
c. In cases without adhesions but with the presence of
imprint.
d.All cases of occludable angle, but with normal IOP
and absence of adhesions and/or imprint.
Answers to clinical scenario: angle-closure glaucoma: diagnosis [published in RAMB
2014; 60(4)]
1. What is the importance of gonioscopy in the diagnosis of patients with angle-closure glaucoma?
This is the most relevant examination for the classification of glaucoma. (Alternative B)
2.What is the role of UBM (Ultrasound Biomicroscopy) in the diagnosis of patients with angle-closure glaucoma?
The apposition of the iris to the outer wall of the camerular sinus has been more frequently detected by
UBM than gonioscopy. (Alternative C)
3.What is the role of AS-OCT (Anterior Segment
Optical Coherence Tomography) in the diagnosis of patients with angle-closure glaucoma?
AS-OCT is useful for quantitative evaluation of the
camerular sinus. (Alternative D)
4. Can AS-OCT replace gonioscopy?
There is greater concordance between the two methods in detecting closed angles in the upper quadrants. (Alternative B)
5.What is the validity of the prone-position test in
dark room in the diagnosis of angle-closure glaucoma?
Checking the probability of angle closure when there is IOP elevation. (Alternative C)
5. Factors involved in the indication of PLI in cases
of suspected primary angle closures include all of
the following, except:
a.Lack of symptoms.
b.Family history of glaucoma or blindness.
c. Patient follow-up capacity.
d.Social and economic status.
398Rev Assoc Med Bras 2014; 60(5):396

Accreditation
Update on late-onset hypogonadism (loh) or adam: diagnosis
Atualização em hipogonadismo masculino tardio (HMT) ou Daem: diagnóstico
Bernardo WM, Martits AM, Costa EMF, Nardi AC, Nardozza Jr. A, Faria G, Facio Jr. FN
http://dx.doi.org/10.1590/1806-9282.60.05.003
1. The main signs and symptoms involved in late-onset male hypogonadism include the following,
except:
a.Erectile dysfunction and decreased libido.
b.Anxiety.
c. Depression.
d.Decreased testicular volume.
4. Tests to be requested before the start of hormone
replacement therapy (art) include the following,
except:
a.Baseline testosterone measurement.
b.Lipid evaluation.
c. Baseline PSA levels.
d.Evaluation of renal function.
2. On the main instruments used in the definition
and diagnostic assessment of male aging, we cannot affirm that:
a.When analyzing the responses to the ADAM questionnaire, clinically suspected cases of LOH are those in
which the symptoms of sexual dysfunction are present.
b.The Smith questionnaire is considered a questionnaire to assess the risk of LOH.
c. It is recommendable for the AMS scale and ADAM
questionnaire to be used as screening instruments.
d.The use of the three instruments makes the diagnosis of HMT through functional and biochemical criteria unnecessary.
5. How should prostate cancer be monitored?
a.Ultrasound-guided prostate biopsy.
b.PSA higher than 4 ng/mL or 3 ng/mL in men with a
high risk of prostate cancer.
c. An increase in PSA levels higher than 1.4 ng/mL in
any 12 month period during treatment.
d.Detection of prostatic abnormality during rectal examination.
3.What is the role of the serum and free testosterone (bat) levels in the diagnosis of late-onset hypogonadism?
a.Free testosterone is a less precise marker of hypogonadism.
b.The result of the total testosterone level does not affect the determination of free testosterone.
c. TT (total testosterone) would not be the ideal measure to assess late-onset hypogonadism.
d.There is a fall in testosterone and BAT levels at 2.3%/
year and 1.1%/year.
Rev Assoc Med Bras 2014; 60(5):399
399
guidelines in focus
Botelho RV et al.
Espondilolistese degenerativa: tratamento cirúrgico
Authorship: Brazilian Society of Neurosurgery; Brazilian Society of Orthopedics and Traumatology
Participants: Ricardo V. Botelho; Noel O. Foni; Alberto O. Gotfryd; Carlos Fernando P.S. Herrero; Jefferson
Daniel; Robert Meves; Marcelo Luis Mudo; Ricardo S. Simões; Sérgio Zylbersztejn; Wanderley M. Bernardo Conflict of interest: no conflict of interest informed.
http://dx.doi.org/10.1590/1806-9282.60.05.004
The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize procedures to assist the reasoning and decision-making of doctors.
The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.
Description of the evidence
collection method
To develop this guideline the following primary and secondary electronic databases were consulted: Medline
(1966-2009), Cochrane, Cochrane Central Register of Controlled Trials – Central, Embase (1980-2010) and Lilacs
(1982-2010). The search for evidence came from actual
clinical scenarios and used keywords (MeSH terms) grouped in the following syntax: surgical procedures, operative, nonsurgical,therapy, lumbosacral region, lumbosacral, degenerative, spondylolisthesis, spondylolisthesis.
The articles were selected after critical evaluation of the
strength of scientific evidence by specialists from the participating Medical Associations, and publications of greatest strength were used for recommendation. The recommendations were drawn from group discussion. The
entire guideline was reviewed by an independent group
specializing in evidence-based clinical guidelines.
Grade of recommendation and strength
of evidence
A.Experimental or observational studies of higher consistency.
B.Experimental or observational studies of lower consistency.
C.Case reports (non-controlled studies).
D.Opinions without critical evaluation, based on consensus, physiological studies, or animal models.
Objective
This guideline’s target audience comprises general practitioners, rheumatologists, orthopedists, physiatrists, neurologists and neurosurgeons in order to be able to guide
patients with lower back pain and/or sciatic pain resis-
tant to non-operative treatment caused by lumbar degenerative spondylolisthesis regarding the indication for
surgical treatment.
Introduction
Degenerative spondylolisthesis refers to a forward slippage
of a lumbar, with an intact neural arch. Uncommon before
the age of 50 years, it is more common in women and particularly in blacks, with a male: female ratio of 1:6 (B).1 L4-L5 is the most commonly affected level and rarely exceeds
30% of the vertebral width. Degenerative spondylolisthesis
is usually asymptomatic but may be associated with symptomatic stenosis of the lumbar spinal canal. The canal stenosis is the most common cause of back surgery in adults
over 65 years when associated with neurogenic claudication.
However, spinal stenosis is usually asymptomatic. Therefore, clinical radiological correlation is essential for making
decisions (A).2 Surgical treatment with spinal decompression and stabilization in spondylolisthesis is recommended
when conservative treatment fails (B).3
How long should conservative treatment
(non-operative) be maintained?
In general, favorable functional outcomes in patients unresponsive to non-operative treatment are reported in
groups with diverse etiologies for degenerative lumbar
stenosis as well as time of conservative treatment (C).4-6
The time tested in this particular group of patients included in the clinical trial was 12 weeks. Patients treated conservatively without success and who underwent surgical
treatment had better progression from a functional point
of view, after 4 years of follow-up (B).7
Recommendation
After 12 weeks of unsuccessful conservative treatment,
surgery is a treatment option for these patients (B).
Is it necessary to refer the patient to
arthrodesis with use of rigid pedicle
screws (non-dynamic)?
The trials below discussed the value of fusion as treatment for spinal stenosis associated on one or two levels
with degenerative spondylolisthesis.
Herkowitz and Kurz8 studied the isolated non-instrumented arthrodesis and showed that fusion produced less
radicular pain (in the lower limbs) and better clinical outcome according to the surgeon’s assessment (B).8 Bridwell
et al.9 compared instrumented and non-instrumented fusion techniques. Patients undergoing instrumented fusion
had less progression of spondylolisthesis and improved
walking ability (B).9 Obtaining solid fusion was associated with subjective improvement. Both studies have methodological limitations: the control group was small (B).8,9
Fishgrund et al.10,11 in a randomized trial done in 1997,
studied the effect of instrumentation on outcomes of spondylolisthesis, either arthrodesed or not. The authors found
that the instrumentation increased the fusion rate but did
not improve clinical outcomes (B).10,11 These studies have
provided conflicting evidence according to which instrumentation would produce significant clinical improvement.
Recommendation
Instrumentation is an option in the treatment of degenerative spondylolisthesis to increase the chance of obtaining solid fusion and improve clinical outcomes (B).
Is the use of bone substitutes such as
BMP (bone morphogenetic protein) safe
and effective in lumbosacral
arthrodesis?
Regarding the rate of fusion, two studies12-14 A compared
the use of osteoinductors (BMP) with iliac graft in patients with degenerative spondylolisthesis (single level),
treated by means of neural decompression and non-instrumented intertransverse arthrodesis, with similar clinical and radiographic results (B). However, there are
many publications and case reports on complications arising from the use of BMP, including bone resorption and
osteolysis, cage/graft migration, heterotopic ossification,
radiculitis, formation of specific antibodies and bruises.15
Prospective and randomized studies are needed to elucidate the best clinical indications and safe dosages for the
use of osteoinductors (BMP) in lumbosacral spine.
Recommendation
Due to the small number of studies on osteoinductors
(BMP) and the high number of complications arising
from their use, it was not possible to recommend its routine use for the treatment of these patients.
What is the most appropriate diagnostic
study in this clinical context?
Plain radiographs in the standing position determine the
diagnosis and the percentage of slippage in degenerative
spondylolisthesis. Being available in most hospitals and
since it is not an invasive test, this is the first additional
test requested (C).16,17 Plain radiographs of the spine are
effective to evaluate the bone structure of the spine and
should be performed in the standing position to be more
accurate in identifying the intervertebral disc height, lumbar lordosis and the degree of slippage between the vertebrae. Plain radiographs in anteroposterior incidence also
allow assessment of the morphology of the articular facets. The lateral view also allows dynamic evaluation of
the stability of the spine with studies of lumbosacral spine in maximum flexion and extension (C).22
Computed tomography is more sensitive and specific in identifying the narrowing of the spinal canal than
plain radiography, because it allows visualization of the
spinal canal in axial view. Myelography or CT myelography is more specific than non-specific CT scans and
is important for the identification of spinal stenosis in
patients with degenerative spondylolisthesis and neurologic symptoms. However, this is a test rarely used
because it is invasive and is associated with adverse effects – secondary to ionizing radiation and contrast injection (C).18,19
In the presence of symptomatic lumbar stenosis, the
most sensitive and specific radiologic examination is MRI,
as it enables the visualization of soft tissues in the spine.
MRI is the most accurate study to analyze the pathological anatomy of the narrowing of the spinal canal – produced by prolapsed intervertebral disc, hypertrophy of the
ligamentum flavum, zygapophyseal joint hypertrophy, and
vertebral slippage with intact vertebral arch (C).20 Dynamic myelography and CT myelography may be indicated to elucidate cases where there is a lack of association
between symptoms and MR imaging for dynamic analysis or the presence of bony component contributing to
the narrowing of the spinal canal. Another possibility for
such an indication is MRI contraindicated in patients
with pacemakers and claustrophobia. Sedation and open
MRI are options for performing the test in patients with
claustrophobia (C).17-21
401
Botelho RV et al.
Recommendation
The most appropriate diagnostic test in this situation is
plain radiography, which is more widely available; however, MRI is indicated for patients with symptomatic lumbar stenosis.
Bone substitutes are equal or superior
to autografts in this situation?
Two randomized trials 23,24 evaluated the association of
bone expander beta-tricalcium phosphate to “local” bone
tissue from the posterior vertebral elements, and compared their achieved results with autologous iliac graft, considered the gold standard in this clinical scenario. Both
studies reported there were no clinical or radiographic
differences between the groups assessed, and the use of
bone expanders avoided the occurrence of pain in the iliac
donor site (A).23,24
Recommendation
The association of local bone graft (from the posterior
vertebral elements) and beta-tricalcium phosphate is a
therapeutic option for the removal of autologous bone
graft from the iliac bone (A).
Should the spondylolisthesis be reduced?
In the search for Keywordsand indexed terms, 388 articles
were retrieved; of these, 47 abstracts, and 3 comparative
clinical trials chosen for analysis. A thorough analysis showed that the three articles were case series with small samples, and two showed a 60% loss on follow-up and conflicting results (C).25-27 Due to the low quality of the articles,
it was not possible to make a recommendation.
Are there any differences among the
various types of arthrodesis?
There are no randomized trials comparing the various
methods of arthrodesis focusing on degenerative spondylolisthesis, especially with regard to intersomatic spacers.
We found that lower-quality observational studies using
different techniques for lumbar fusion and heterogeneous
study populations showed a higher fusion rate in patients
undergoing circumferential arthrodesis, but without evidence of better functional results (B).28-30
Recommendation
There are no randomized trials comparing the various
methods of arthrodesis and use of intersomatic spacers
in cases of degenerative spondylolisthesis; thus, it is not
possible to recommend a specific technique (B).
References
1. Jacobsen S, Sonne-Holm S, Rovsing H, Monrad H, Gebuhr P. Degenerative
lumbar spondylolisthesis: an epidemiological perspective: the Copenhagen
Osteoarthritis Study. Spine 2007;32:120-125.
2. Boden SD, Davis DO, Dina TS, Patronas NJ, Wiesel S. Abnormal magneticresonance scans of the lumbar spine in asymptomatic subjects: a prospective
investigation. J Bone Joint SurgAm 1990;72:403-408.
3. Weinstein JN, Lurie JD, Tosteson TD, Hanscom B, Tosteson ANA, Blood
EA, et al. Surgical versus Nonsurgical Treatment for Lumbar Degenerative
Spondylolisthesis.NEngl J Med 2007; 356:2257-2270.
4. Atlas SJ, Keller RB, Wu Ya, et al. Long-term outcomes of surgical and
nonsurgical management of lumbar spinal stenosis: 8 to 10 year results
from the Maine lumbar spine study. Spine 2005;30:936.
5. Johnsson K, Udén A, Rosén I. The effect of decompression on the natural
course of spinal stenosis: a comparison of surgically treated and untreated
patients. Spine 1991;16:615.
6. Simotas AC, Dorey FJ, Hansraj KK, et al. Nonoperative treatment for lumbar
stenosis: clinical and outcome results and a 3-year survivorship analysis.
Spine 2000;15:197.
7. Weinsteinetal JN. Surgical Compared with Nonoperative Treatment for
Lumbar Degenerative SpondylolisthesisJ Bone Joint Surg Am. 2009;91:1295304.
8. Herkowitz HN, Kurz LT. Degenerative lumbar spondylolisthesis with spinal
stenosis. A prospective study comparing decompression with decompression
and intertransverse process arthrodesis. J Bone Joint Surg Am. 1991
Jul;73(6):802-8.
9. Bridwell KH, Sedgewick TA, O’Brien MF, Lenke LG, Baldus C.The role of
fusion and instrumentation in the treatment of degenerative spondylolisthesis
with spinal stenosis. J Spinal Disord 1993;6:461-72.
10. Fischgrund J, McKay M, Herkowitz H, Brower R, Montgomery D, Kurz L.
Degenerative lumbar spondylolisthesis with spinal stenosis: A prospective,
randomized study, comparing decompression and fusion with and without
posterior pedicular instrumentation. Orth Trans 1997;21:158.
11. Fischgrund JS, Mackay M, Herkowitz HN, Brower R, Montgomery DM,
Kurz LT. Degenerative lumbar spondylolisthesis with spinal stenosis: A
prospective, randomized study comparing decompressive laminectomy and
arthrodesis with and without spinal instrumentation. Spine1997;22:2807-12.
12. Hwang CJ, Vaccaro AR, Hong J, Lawrence JP, Fischgrund JS, Alaoui-Ismaili
MH, et al. Immunogenicity of osteogenic protein 1: results from a prospective,
randomized, controlled, multicenter pivotal study of uninstrumented lumbar
posterolateral fusion. J Neurosurg Spine. 2010;13(4):484-93.
13. Vaccaro AR, Anderson G, Patel T, Fischground J, Truumees E, Herkowitz
HN, et al. Comparison of OP-1 Putty (rhBMP-7) to iliac crest autograft for
posterolateral lumbar arthrodesis: a minimum 2-year follow-up pilot study.
Spine.2005;(24):2709-16.
14. Kanayama M, Hashimoto T, Shigenobu K, Yamane S, Bauer TW, Togawa
D. A prospective randomized study of postero lateral lumbar fusion using
osteogenic protein-1 (OP-1) versus local autograft with ceramic bone
substitute: emphasis of surgical exploration and histologic assessment.
Spine. 2006;31(10):1067-74.
15. Mroz TE, Wang JC, Hashimoto R, Norvell DC. Complications related to
osteobiologics use in spine surgery: a systematic review. Spine. 2010;35(9S):86104.
16. Fischgrund JS, Mackay M, Herkowitz HN, Brower R, Montgomery DM,
Kurz LT. 1997 Volvo Award winner in clinical studies. Degenerative lumbar
spondylolisthesiswith spinal stenosis: a prospective, randomized study
comparing decompressive laminectomy and arthrodesis with and without
spinal instrumentation. Spine. 1997;22(24):2807-2812.
17. Kanayama M, Hashimoto T, Shigenobu K, Oha F, Ishida T, Yamane S.
Intraoperative biomechanical assessment of lumbar spinal instability:
validation of radiographic parameters indicating anterior column support
in lumbar spinal fusion. Spine. 15 2003;28(20):2368-2372.
18. Rosenberg NJ. Degenerative spondylolisthesis. Predisposing factors. J Bone
Joint Surg Am. 1975;57(4):467-474.
19. Postacchini F, Perugia D. Degenerative lumbar spondylolisthesis.Part I:
Etiology, pathogenesis, pathomorphology,and clinical features. Ital J
OrthopTraumatol.1991;17(2):165-173.
20. Guglielmi G, De Serio A, Leone A, Agrosì L, Cammisa M. Imaging in
degenerative disease of the lumbar spine. Rays. 2000 Jan-Mar;25(1):19-33.
21. Corinthian Diagnostic Radiology, New York, NY, USA. Lumbar spinal
stenosis assessment with computed tomography, magnetic resonance
imaging, and myelography.ClinOrthopRelat Res. 2001 Mar;(384):12236.
22. Ohomori K. Clinical application of a novel assessment for lumbosacral
stability J Neurosurg 2009 JUn 10(¨6) 587-594.
23. Gunzburg R, Szpalski M. Use of a novel beta-tricalciumphosphatebasedbonevoidfiller as a graftextender in spinal fusion surgeries. Orthopedics.
2002;25(5):591.
24. Dai LY, Jiang LS. Single-level instrumented posterolateral fusion of lumbar
spine with beta-tricalcium phosphate versus autograft: a prospective,
randomized study with 3-year follow up. Spine. 2008;33:1299-304.
25. Setti SR,Raju B. Reduction of spondylolisthesis Neurosurg Focus 13 (1):2,
2002.
26. Haka J, Wroñski J. The role of reduction in operative treatment of
spondylolytic spondylolisthesis Neurologia i Neurochirurgia Polska 2008;
42, 4: 345–352.
27. Matthiass HH, Heine J. The surgical reduction of spondylolisthesis. Clin
Orthop 1986; 203: 34-44.
28. Umeta RS, Avanzi O. Techniques of lumbar-sacral spine fusion in spondylosis:
systematic literature review and meta-analysis of randomized clinical trials.
Spine J. 2011 Jul;11(7):668-76. Epub 2011 Jun 8.
29. Han X, Zhu Y, Cui C, Wu YA. Meta-analysis of circumferential fusion versus
instrumented posterolateral fusion in the lumbar spine. Spine. 2009 Aug
1;34(17):E618-25.
30. Zhou ZJ, Zhao FD, Fang XQ, Zhao X, Fan SW. Meta-analysis of instrumented
posterior interbody fusion versus instrumented posterolateral fusion in the
lumbar spine. J Neurosurg Spine. 2011 Sep;15(3):295-310. Epub 2011 May 27.
403
guidelines in focus
Martits AM et al.
Hipogonadismo masculino tardio ou Daem: tratamento
Authorship: Brazilian Society of Endocrinology; Brazilian Society of Urology
Participants: Martits AM, Costa EMF, Nardi AC, Nardozza Jr. A, Facio Jr. FN, Faria G, Bernardo WM
Conflict of interest: no conflict of interest informed.
Final draft: March 21st, 2014
http://dx.doi.org/10.1590/1806-9282.60.05.005
The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field in order to standardize procedures to assist the reasoning and decision-making of doctors.
The information provided through this project must be assessed and criticized by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical status of each patient.
Description of the evidence collection
method
The recommendations were supported by the evidence obtained in the Medline, Embase, Lilacs and Cochrane databases, using the following strategies: ((((((aged OR aging)
AND (androgens/deficiency OR hypogonadism OR testosterone/deficiency)) AND (hormone replacement therapy)
AND (aging/blood OR androgens/blood* OR androgens
OR androstenedione/blood OR body mass index OR body
Weight OR dehydroepiandrosterone/blood* OR dehydroepiandrosterone sulfate/blood* OR dihydrotestosterone/
blood OR gonadal steroid hormones/blood* OR gonadotropins/blood OR gonadotropins OR pituitary hormones
OR hormones/blood* OR hormones/physiology OR hypogonadism/blood OR hypotalamo-hypophyseal system OR
immunoassay OR luteinizing hormone OR luteinizing
hormone/blood OR radioimmunoassay OR radioimmunoassay/methods OR radioimmunoassay/standards* OR
reagent kits, diagnostic/standards OR sex hormone-binding globulin/analysis OR testosterone OR testosterone/
blood* OR testosterone/metabolism OR hematocrit OR
liver function tests OR prostatic neoplasms OR continuity
of patient care OR consultation OR monitoring))) AND
(diagnosis/broad[filter]) AND (“last 5 years”[PDat]))) OR
(((((aged OR aging) AND (androgens/deficiency OR hypogonadism OR testosterone/deficiency)) AND (hormone
replacement therapy) AND (aging/blood OR androgens/
blood* OR androgens OR androstenedione/blood OR
body mass indexOR body weight OR dehydroepiandrosterone/blood* OR dehydroepiandrosterone sulfate/blood*
OR dihydrotestosterone/blood OR gonadal steroid hormones/blood* OR gonadotropins/blood OR gonadotro-
pins OR pituitary hormones OR hormones/blood* OR
hormones/physiology OR hypogonadism/blood OR hypotalamo-hypophyseal system OR immunoassay OR luteinizing hormone OR luteinizing hormone/blood OR radioimmunoassay OR radioimmunoassay/methods OR
radioimmunoassay/standards* OR reagent kits, diagnostic/standards OR sex hormone-binding globulin/analysis
OR testosterone OR testosterone/blood* OR testosterone/metabolism OR hematocrit OR liver function tests OR
prostatic neoplasms OR continuity of patient care OR consultation OR monitoring))) AND (etiology/broad[filter])
(age OR aged OR aging) AND (andropause OR gonadal
OR deficiency OR hypogonadism OR hypogonadal) AND
(testosterone OR androsterone OR DHEA OR dehydroepiandrosterone OR androgen OR androgenic OR nandrolone OR replacement OR steroids OR anabolic OR sex OR
hormone) AND (muscles OR strength OR cognitive OR
function OR cognition OR mental OR performance OR
diabetic OR diabetes OR obesity OR body OR fat OR obese OR mass OR hyperinsulinaemia OR adiposity OR libido OR sexual OR behavior OR quality of life OR life style
OR lipids OR carbohydrates OR metabolism) (((age OR
aged OR aging) AND (andropause OR gonadal OR deficiency OR hypogonadism OR hypogonadal) AND (testosterone OR androsterone OR DHEA OR dehydroepiandrosterone OR androgen OR androgenic OR nandrolone OR
replacement OR steroids OR anabolic OR sex OR hormone))) AND (polycythemia OR prostatic neoplasms OR cardiovascular diseases OR liver diseases OR sleep apnea syndromes OR metabolic syndrome).
Grade of recommendation and strength
of evidence
A: Experimental and observational studies with high consistency.
B: Experimental and observational studies with low consistency.
C: Case reports (non-controlled studies).
D: Opinions without critical evaluation, based on consensus, physiological studies, or animal models.
Objective
To recommend evidence-based approaches to treat late-onset hypogonadism.
Introduction
The benefits of androgen replacement therapy in hypogonadal young men are well documented, especially given that the restoration of testosterone concentrations
to normal limits maintains and restores sexual function,
energy, mood, the development of muscle mass and increases bone mass. However, the cost/benefit relationship
of testosterone replacement in Androgen Deficiency in
the Aging Male (ADAM) remains controversial (A).1
What is the role of androgen
replacement therapy (ART) to restore
bone mass, muscular strength and body
composition?
There is no doubt that ART has a positive effect on bone
mass. The treatment with testosterone determines a significant improvement in bone mass in hypogonadal men
of all ages (B).2 This effect becomes even more evident the
longer the treatment time and the more severe the hypogonadism (A).3
The effects of ART on muscular strength in men with
ADAM are generally evaluated indirectly through analysis
of the performance of physical activities and body composition. Therefore, the use of transdermal testosterone at a
dose of 50mg/day for a 6 month period has been shown
to be capable of increasing muscular strength and lean
mass in patients, improving their physical function and
quality of life (A).4 Direct evaluation of muscle size in elderly patients with chronic diseases with a loss in muscle mass and ADAM have shown that testosterone therapy in older patients leads to an increase in muscle size
and improved muscular strength, improving performance in physical activities (B).5
The most reproducible effect of testosterone treatment is the increase in lean mass both in hypogonadal
patients and healthy males. Even if for a short period of
time, transdermal testosterone treatment increases muscle mass in hypogonadal men aged over 40 years (A)3(B).6
On the other hand, studies evaluating the reduction
in body fat as a direct effect of testosterone treatment are
controversial. A slight reduction in body fat in patients
being treated has sometimes been observed (A).3 Testosterone treatment results in a significant reduction in
waist circumference, which is an indicator of visceral fat
(A).7 However, this benefit has not been shown in short
acting treatments (A).8
The reduction in BMI and waist circumference may
not occur in all patients, but the reduction in visceral fat
is evident when analyzed directly using magnetic resonance imaging. Therefore, testosterone therapy selectively reduces the accumulation of visceral fat, though the
change in total body composition is not observed in all
patients (B)6 (A).9
This discrepancy in the findings in relation to the effects of testosterone on the reduction of lean mass may
be related to the dose or route of testosterone administration, or the direct effect of testosterone on the increase in lean mass. Ultimately, testosterone replacement improves the body composition of patients with low levels
of the hormone (B).2
The use of GH in association with testosterone appears to present a synergic effect on the improvement in
body composition, muscular strength and, consequently,
the quality of life of men with ADAM, and can be a treatment option to be considered in such patients (A).10,11
Recommendation
Testosterone replacement therapy improves bone mass,
muscular strength and body composition in patients with
ADAM and the effects increase with the length of treatment and severity of hypogonadism. The use of testosterone in patients with ADAM is strongly recommended
to increase bone mass, muscular strength and body composition.
replacement therapy (ART) to restore
libido and sexual function?
The effectiveness of testosterone replacement therapy on
sexual symptoms has been well established, regardless of
the route of administration; nevertheless, the works are
controversial in relation to the effectiveness of the oral
route. Treatment with testosterone, regardless of the route of administration, improves and restores the libido in
men with lower testosterone levels (B)12-15 in the first three months of treatment (C).16 However, testosterone does
405
Martits AM et al.
not seem to have an effect on the sexual function of eugonadal males (B).12 Long acting injectable testosterone
has demonstrated greater tolerability and more physiological action (B),15 while the oral form was not effective
in improving sexual symptoms (A).17
Studies suggest a direct relationship between free
testosterone and vasodilation of the corpora cavernosa. As
such, testosterone therapy presents a synergic effect on
patients with ADAM that have responded partially to
phosphodiesterase inhibitors, significantly improving
erectile dysfunction in such patients (B).12,13,18 Ultimately,
when erectile dysfunction does not respond to testosterone treatment, the combination of phosphodiesterase
inhibitors should be considered (B).2
Not only testosterone but also DHEA has been considered an important androgen for adequate sexual function,
although its effectiveness in improving sexual symptoms
and erectile dysfunction has not been demonstrated (A).19
Recommendation
Testosterone replacement therapy is recommended for
improving libido and sexual function only in patients
with low testosterone levels. The use of testosterone is recommended for improving the libido and sexual function of patients with ADAM.
replacement therapy (ART) to improve
mood, quality of life and cognitive
functions?
The influence of testosterone replacement therapy on the
quality of life of older men has been widely evaluated. Although the majority of studies do not have good evidence, an important improvement on quality of life after testosterone replacement has been suggested in both
hypogonadal and eugonadal men.
Comparing the quality of life of men with ADAM
that use testosterone with those that do not, the improvement in the quality of life of the group using testosterone
could be relative, i.e. determined by the decline in quality
of life of the placebo group, suggesting a possible positive effect of testosterone on preventing the decline in quality of life with age (A).3 Furthermore, the improvement
of physical function and control and somatic and sexual
symptoms with testosterone replacement improves the
quality of life of patients with ADAM, and may constitute an important treatment strategy in old age (A)4(B).5
The effects of testosterone replacement on cognitive functions, mood and sense of wellbeing in men with
ADAM are not yet clear. However, studies with excellent
evidence have demonstrated that regardless of the route
of administration, dose or treatment time, testosterone
replacement does not affect cognitive function, mood or
quality of life in men with ADAM (A)20,21 (B).22
Recommendation
Testosterone replacement improves mood and quality of
life in men with ADAM; however, there is no evidence of
a direct effect of testosterone over the above, or over cognitive function. It is strongly recommended not to use
testosterone to specifically improve mood, quality of life
or cognitive functions in men with ADAM.
What is the influence of androgen
replacement therapy (ART) on the
metabolism of carbohydrates and lipids?
Hyperinsulinemia and insulin resistance (IR) are antecedents of type 2 diabetes mellitus (T2DM) and metabolic
syndrome, which in turn is characterized by IR associated with changes in lipid profile, among others. Type 2
diabetes is often associated with male hypogonadism, and
it has also been suggested that testosterone replacement
improves glycemic control as well as the body fat in patients with T2DM (B).23
Replacement therapy with injectable testosterone has
been shown to be effective in improving insulin resistance and glycemic control with a significant reduction in
fasting blood glucose and glycated hemoglobin (HbA1c)
in hypogonadal men with type 2 diabetes (A)7 or metabolic syndrome (C).16 Similar efficacy has also been observed in the metabolic syndrome parameters, with a significant reduction in waist circumference, blood pressure,
total cholesterol, LDL and triglycerides and an increase
in HDL levels, albeit without changes in the dietary patterns (C).16 An additional effect to that described above has been observed in the administration of long-acting testosterone. Patients with metabolic syndrome and
ADAM achieved a dramatic reduction in the levels of insulin, leptin, HOMA-R and inflammatory markers such
as IL-1b, TNFa and PCR (A).9
The association of testosterone with an aromatase
inhibitor leads to a significant increase in the testosterone/estradiol ratio and thereby a significant reduction in
triglyceride levels in such patients. Therefore, this combination may be particularly useful in patients with hypertriglyceridemia. However, the safety of the use of this
association has not yet been established (A).24
Ultimately, the effects of testosterone on carbohydrate and lipid metabolism are still uncertain. Testosterone
treatment in hypogonadal men with type 2 diabetes and/or
metabolic syndrome can lead to (yet unproven) benefits
for their metabolic state (B).2
There is speculation about the role of the age-related
decrease in DHEA on the metabolism of carbohydrates.
The few studies that have addressed this issue suggest that
DHEA has no effect on the metabolism of carbohydrates (B).25
Recommendation
The effects and benefits of testosterone replacement on
the metabolism of carbohydrates and lipids are still controversial. Testosterone replacement is recommended
in men with ADAM and metabolic syndrome as an adjunctive to improve the metabolic profile of such patients.
What is the risk of ART in relation to
exacerbating prostate disease?
Unfortunately, to date there is no consensus on the response pattern of PSA to testosterone therapy. It has been
argued that a significant increase in PSA after beginning
testosterone replacement can be a sign of prostate cancer. However, most studies do not support this argument.
Historically, TRT has been absolutely contraindicated in men with a suspected or confirmed diagnosis of
prostate cancer. There is evidence that TRT can stimulate growth and aggravate the symptoms of prostate cancer in men with active disease.
TRT causes a mild increase in PSA in most patients
without prostatic changes and such increase does not
depend on patient age, mode of replacement, or baseline PSA levels and total free testosterone (B).26 In intra-prostatic cancer patients with normalization of PSA after permanent brachytherapy or external beam radiation
therapy who developed hypogonadism, testosterone treatment determined a slight increase in PSA with no signs of
recurrence or progression of the cancer (C),27,28 while in
those submitted to radical prostatectomy, PSA levels did
not change (B).29 In all these studies, testosterone levels
were maintained within the normal range. On the other
hand, when serum testosterone levels are kept above the
normal values in patients previously treated for prostate
cancer, even with the association of 5-a-reductase inhibitors, PSA levels rise significantly (B).30
In patients who received curative treatment for low risk localized prostate cancer with the radical prostatectomy and/or
radiotherapy, with no evidence of active disease, the risks
and benefits of TRT should be assessed. There is no consensus on the moment for determining consolidated healing treatments with this intention in localized prostate can-
cer. Short-term studies with few patients suggest that after 1
year of treatment TRT can commence if the patient is cured.
The data available in the literature indicate that:
1. The incidence of prostate cancer in men with late-onset hypogonadism on TRT is no greater than the population in general (B);31
2. TRT in older men with late-onset hypogonadism
seems to have a slight effect on prostate tissue (A);32
3. In patients with prostate cancer treated using radical prostatectomy, brachytherapy or radiotherapy,
TRT can be used with caution, and patients should
be constantly monitored (C);27,28
4. High doses of testosterone, even if associated with
5-alpha-reductase inhibitors, cause a significant increase in PSA (B).30
The greatest risk of prostate cancer has been observed in
men with higher estrone levels (A);33 however, studies with
a higher number of patients should be conducted to confirm this observation.
Recommendation
Maintaining testosterone at physiological levels increases PSA levels, but does not increase the incidence of prostate cancer. Men successfully treated for prostate cancer
and diagnosed with hypogonadism are candidates for
TRT after a prudent interval for observation, and there
is no clinical or laboratory evidence of recurrence of the
disease. The risks and benefits of TRT should be clearly
understood by the patient and treatment should be carefully monitored. The safety data in this clinical situation
are still limited. Maintaining physiological serum levels
of testosterone and monitoring PSA in all patients on testosterone replacement is recommended.
What is the role of ART in the increased
risk of cardiovascular disease?
The effects of TRT on cardiovascular risk appear to be associated with the adverse effects on polycythemia, lipid
profile and sleep apnea. On the other hand, TRT leads to
a decrease in BMI and improves the lipid profile, providing cardiovascular benefit (B).31 The maintenance of serum testosterone levels within the normal range does not
lead to significant changes in hemoglobin and lipid profiles, decreasing the risk of developing polycythemia and
consequently cardiovascular and vascular events (B).34,35
Hyperinsulinemia and insulin resistance (IR) are essential components of metabolic syndrome, which in
turn is associated with an increased cardiovascular risk.
TRT improves the components of metabolic syndrome
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Martits AM et al.
in hypogonadal patients with T2DM, reducing the cardiovascular risk (A).36
Recommendation
There is no evidence that TRT per se increases cardiovascular risk. It is recommendable to maintain serum testosterone levels within the normal range so that cardiovascular risk factors such as polycythemia and insulin
resistance are minimized, thereby reducing overall cardiovascular risk.
What is the risk of polycythemia on ART?
Secondary polycythemia is a major adverse event of TRT.
Several authors have demonstrated its occurrence, and it
is related to the maintenance of high serum levels of testosterone, regardless of the treatment time (B).31,34,35 Therefore, the evidence available so far indicates that the
maintenance of serum testosterone levels within the normal average does not lead to polycythemia (B).37
Recommendation
The appearance of polycythemia is directly related to supraphysiological serum testosterone levels. It is recommended to monitor hemoglobin and hematocrit in all
patients on TRT and to maintain serum testosterone levels within the normal range to minimize the risk of
polycythemia.
What is the hepatotoxicity of ART?
Hepatotoxicity due to TRT is a rare event limited almost
exclusively to the use of oral 17a-alkylated preparations
such as fluoxymesterone and methyltestosterone, which
are highly hepatotoxic and can cause the development of
hepatocellular adenomas, liver carcinomas, cholestasis
and hemorrhagic cysts of the liver (A).1 The long term
use of other testosterone preparations does not lead to a
change in hepatic function among men with late-onset
hypogonadism (B).31,35
Recommendation
17a-alkylated oral preparations such as methyltestosterone and fluoxymesterone present hepatotoxicity. It is
not recommended to monitor the liver function of patients on TRT with any other pharmaceutical form.
What is the effect of ART on sleep
apnea? Are there other side effects?
Testosterone replacement has been associated with the
onset or worsening of sleep apnea in men treated with
high doses of testosterone (A).1 The administration of
testosterone in patients with sleep apnea and erectile dysfunction associated with low testosterone improves sexual symptoms and does not worsen sleep apnea (C).38
Gynecomastia is a benign, infrequent and generally
reversible complication, a result of the aromatization of
testosterone into estradiol in peripheral tissues. Infertility and decreased testicular volume are related to supraphysiological doses of testosterone. Sodium and water
retention may occur during replacement and generally
present clinical significance in patients with cardiac decompensation, hypertension or renal failure. Skin reactions such as erythema and itching are common with the
use of patches. Intramuscular injections may cause local pain, lumps, rashes and boils. Acne, oily skin, increased body hair and skin “flushing” are benign and reversible complications that do not cause major concern (A).1
Recommendation
The side effects of TRT, such as worsening or onset of
sleep apnea, gynecomastia, infertility, fluid retention and
skin changes are directly related to supraphysiological levels of serum testosterone. It is strongly recommended
to maintain serum testosterone levels within the average
normal range to minimize the occurrence of these side
effects.
What is the role of ART in metabolic
syndrome?
The maintenance of serum testosterone levels within the
normal range leads to improvements in the markers of
metabolic syndrome, such as waist circumference, and
increased levels of HDL without causing polycythemia
or changes in prostatic parameters. This improvement is
not as significant when testosterone levels are maintained at the lower limit of normality (B).37 TRT does not
depend on the pharmaceutical form of testosterone used
or the route of administration and is effective to improve metabolic syndrome parameters; when testosterone levels are maintained within a normal range, however, the
improvement is more significant (B).39 In T2DM patients,
TRT reduces insulin resistance, improves glycemic control, and reduces visceral adiposity and total cholesterol,
which are all components of metabolic syndrome (A).36
The beneficial effects of ART on metabolic syndrome
components appear to be specific to testosterone, given
that chronic replacement with DHEA does not improve
the secretion or action of insulin and postprandial glycemia in women and elderly men (B).40
Recommendation
There is strong evidence that testosterone replacement
improves the parameters of metabolic syndrome, especially if serum levels are maintained within normal limits.
We recommend maintaining serum testosterone levels
within a normal range to aid in the treatment of metabolic syndrome.
Recommendation
Oral testosterone undecanoate does not present hepatotoxicity; however, it has proved ineffective in maintaining
adequate serum testosterone levels, and has variable absorption between individuals. It is strongly recommended NOT to use oral formulations of testosterone and
other androgens as an alternative to TRT.
How should ART be administered orally?
Oral testosterone formulations have been developed to
replace injectable forms; however, some disadvantages
have been noted, such as variable absorption, low bioavailability due to liver metabolism and the need for 2 to
3 daily doses (D).41 Moreover, 17a-alkylated derivatives
are hepatotoxic (A)1 (D)41 and have already been withdrawn
from the American market (A).19 Oral testosterone undecanoate (OTU), the only available oral formulation, is
preferably absorbed in chylomicrons, avoiding the primary hepatic passag (D)41 and significantly reducing hepatotoxicity (A).17 Although most of the studies were flawed due to the small number of participants or the
variability of the dose used, the effectiveness of oral ART
is questionable. Several authors have shown that the OTU,
even at appropriate doses (160 mg/day) was not effective in improving sexual function, wellbeing, sleep disturbances, cognitive function, mood and quality of life in
men with ADAM (A).17,19,20 The manufacturer’s recommendation is for OTU to be taken during meals, yet there is variability in absorption depending on the composition of the patient’s diet (A).19
DHEA has been proposed as an alternative oral ART,
but the results are controversial. Morales et al.19 demonstrated that the ingestion of 50 mg of DHEA orally twice a day, although leading to satisfactory serum levels
did not improve the sexual function of men with ADAM
(A).19 On the other hand, replacement with lower doses
of DHEA (75 mg/day) improved insulin resistance in the
individuals treated (B).42
Another way to release testosterone orally is oral mucosa patches which contain 30 mg of testosterone that
should be administered twice daily. In general, studies
show that this form of ART is capable of maintaining
physiological levels of serum testosterone, is safe and well
tolerated, and is an interesting option for ART in hypogonadal men (D)41(B).43,44
The underreported sublingual form of testosterone administration should be used at a dose of 2.5 mg or
5 mg, 3 times a day. It is rapidly absorbed and metabolized, and it does not lead to a sustained increase in serum
levels of dihydrotestosterone (DHT) and estradiol (D).41
How should ART be administered
transdermally?
Transdermal administration of ART includes patches,
cutaneous gels and cutaneous solutions.
The patches may be non-scrotal or scrotal, which are
thinner and have more effective testosterone absorption
than the non-scrotal version. The first presentation of
transdermal testosterone was the scrotal patch with release of 4 or 6 mg testosterone/day. It should be applied
once daily on depilated scrotal skin (D).41 The most commonly used patches are non-scrotal, releasing 5 mg/day
of testosterone and should be applied once a day on clean
and dry glabrous skin (B).43
Due to the large number of patches on the international market from different manufacturers, in the opinions of the authors, the tolerability of patients is quite
variable due to local adverse effects. They are considered
large and uncomfortable to use, and some formulations
cause local reactions and exhibit low adhesion that ends
up causing low acceptability by patients (B).43 There are
reports of patients who have discontinued treatment due
to allergic reactions at the application site, even when
using a local corticosteroid ointment (B).44
On the other hand, the authors are unanimous regarding the efficacy and safety of this type of ART. The
transdermal patches available provide physiological and
constant levels of serum testosterone, and mimic the circadian rhythm. At a dose of 5 to 7.5 mg/day, changing
patches every 48 hours, they are capable of producing a
significant improvement in symptoms and quality of life
of patients with ADAM (A)8 (B).45-47 With respect to security, Raynaud et al.44,47 reported that the use of transdermal patches showed no negative impact on the hematocrit
and lipid profile of patients (B),45 and does not contaminate other people or the environment (B).47
Many patients prefer transdermal gels or solutions as
they are easy to apply, substantially free of local reactions
and do not require injections (D).41 Testosterone gel formulations available on the health market are available in
the concentration of 1% as “pumps”, so that each “puff”
releases 1.25 g of product; individual 2.5 g and 5 g packages or single dose tubes containing 5 g of the product.
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Martits AM et al.
The recommended dose for starting treatment is 5 g/day,
which can be increased up to 10 g/day (D).48
Testosterone gel should be applied in the morning
on dry skin on the shoulders, arms or abdomen. Patients
should wash hands well after application and let the application site dry before putting on clothes. It is recommended to wait 4 hours after application to bathe or swim.
The application site should be washed with soap and water if there is direct contact with another person (D).48
Testosterone gels at the recommended doses are able
to restore the physiological serum testosterone levels but
they do not mimic the circadian rhythm (B)46 and promote
a significant improvement of sexual symptoms and quality of life for patients with ADAM (B).13 Even at higher
doses (60 mg) applied once daily they promote testosterone levels within the normal range in most patients (B).49
The association of this type of ART with sildenafil at
the maximum dose (100 mg/day) improves erectile dysfunction in hypogonadal men who do not respond to treatment with testosterone alone (B),50 or sildenafil alone (B).49
Transdermal testosterone solution at 2% for axillary
use is a new treatment option with characteristics similar to those described for gels (B).51
A less frequently used form of transdermal ART is the
use of dihydrotestosterone gel. Few studies are available
for this type of ART. The dose of DHT gel is 70 mg/day
for 3 months in patients with ADAM proved to be safe,
but with limited effect on physical and cognitive functions. A greater number of long-term studies with a greater numbers of patients are needed to confirm the safety
and efficacy of DHT as a treatment option for ART (A).52
and free testosterone with no severe adverse effects (B).53
The gel produced in Germany was applied both on scrotal and non-scrotal skin and removed after 10 minutes
in hypogonadal men. There was better tolerability than
the commercial gels, less chance of interpersonal transfer due to early removal of the gel and an effective increase in testosterone levels (B).54
Recommendation
There is strong evidence that transdermal testosterone replacement (patches, gels or solution) is safe and effective
in addition to being the most physiological. Patches, in
turn, are capable of mimicking the circadian rhythm of
testosterone secretion; however, these pharmaceutical forms
are not available in our country. The use of transdermal
TRT is recommended for being the most physiological.
How should injectable ART be
administered?
Is there a difference between the
commercial gel and compound gel?
There are no scientific studies comparing commercial gels
and compound ones. Only two studies have compared
gels that are produced in two different countries that are
not widely available in the global market. The ointment
produced in Japan was used on 50 patients with ADAM
at a dose of 3 mg twice daily on the skin of the scrotum
for 12 weeks and caused a physiological increase in total
Recommendation
Studies with a good level of evidence using noncommercial testosterone gel are still scarce. The use of a testosterone gel preparation without proven efficacy and safety
is not recommended.
How should ART be administered using
subcutaneous implants?
Subcutaneous implants are composed of 1,200 mg of crystallized testosterone, are generally more accepted by patients,
but require a surgical procedure and if not performed by experienced physicians may have high rates of extrusion (B).43
The implants are changed every 3-6 months and are considered safe in long-term studies (B).34 Experience with this
type of ART is still limited in the literature.
Recommendation
Studies with a good level of evidence for this form of TRT
are scarce and this pharmaceutical form is not available
in our country. We recommend not using subcutaneous
testosterone implants until a larger number of studies
on safety and efficacy can be found, as the extrusion rate
appears to be high.
Injectable testosterone preparations have been widely
used for many years. They consist of various testosterone esters, combined or otherwise, namely, propionate,
phenylpropionate, enanthate, cypionate, decanoate, isocaproate and undecanoate (D).41 All formulations are available in Brazil, except those containing testosterone enanthate (B).55 All injections with testosterone esters have
short action, except for testosterone undecanoate depot
(TUD).
The short acting formulations must be injected every
14-21 days while the long acting ones should be applied
every 6 weeks at the start of the treatment and every 12
weeks thereafter (D)41 (B).55 Replacement therapy using
short acting testosterone for a short period of time has
proven effective and safe, improving sexual function in patients without increasing hematocrit or PSA (D)41 (B).55,56
In relation to TUD, in order to achieve adequate serum levels, the second injection should be given after 6
to 10 weeks, with the interval subsequently extended up
to 10-14 weeks (B).57 It is recommended to apply the second injection after 6 weeks and then one injection every
12 weeks (B)15,58,59 (C). 16 It is usually well tolerated and
changes in the actions and side effects are more frequently observed in obese patients (B).57
There are two presentations of TUD – the formulation
available in the USA contains 750 mg of TUD, maintains
serum testosterone levels within the normal range during
an interval of 10 weeks between doses and has proven to
be safe and effective (B).60 1000 mg TUD is available in
Europe and South America, including Brazil. Its pharmacokinetics enables one injection every 12 weeks to be able
to maintain physiological levels of serum testosterone without causing peaks above normal (B).55
Recommendation
Although not the most physiological, the short acting injectable forms have proven safe and effective over time,
but with the disadvantage of fortnightly application. Besides providing physiological levels of testosterone, the
pharmacokinetics of TUD enables quarterly applications,
but with the disadvantage of having a high cost. Among
the available injectable forms, the use of TUD to maintain physiological levels of testosterone is recommended
in order to minimize side effects with fewer injections.
Are there comparative studies between
them? What is the best form of ART?
The criterion to assess efficacy of ART is that testosterone
levels are maintained within normal limits during the 24
hour interval between two applications (WHO, 1992). The
various testosterone formulations differ mainly in relation
to the route of administration and the pharmacokinetics of
the components, causing variability in their effectiveness.
Several authors have carried out comparative studies
between them. In men with ADAM and metabolic syndrome, treatment with TUD demonstrated greater effect
on sexual symptoms and metabolic syndrome parameters
than testosterone gel (A)36 (B),38 while the safety parameters were similar in both modalities (B).38
A 30 weeks follow-up of patients who used short acting TUD or testosterone enanthate showed that the effects of the two formulations were similar, although treatment with TUD requires only four injections per year to
maintain testosterone levels within the physiological range. Polycythemia was not observed in patients who used
TUD (B).15
The comparison of the pharmacokinetics and tolerability of oral patches and non-scrotal skin patches showed that the oral system promotes physiologic levels of
testosterone at a higher percentage of the day than conventional skin patch systems (B).43
A comparative study between the ART and skin patches at the maximum dose (4.8 mg every 48 hours – 2
patches) and short acting testosterone (250 mg every 3
weeks) showed that the percentage of patients who maintained stable and physiological levels of testosterone was
higher in those using patches than in patients who used
injectable testosterone, with high variability in the testosterone levels (B).44
The effects of the three injectable formulations available in Brazil (two with short acting esters and one with
TUD) were compared and it was found that the three formulations are effective in raising testosterone levels and
clinically improving hypogonadal patients, with TUD –
even though, more expensive – being clinically and laboratorially more effective. The three options were shown
to be safe without significantly increasing hematocrit, hemoglobin and PSA (B).55
The treatment of hypogonadal patients with short acting injectable testosterone at doses of 100-200 mg/week
who were subsequently submitted to treatment with testosterone gel at a dose of 5-10g gel/day demonstrated
that testosterone gel produced stable concentrations of
testosterone and improved the quality of life of patients
compared to injectable testosterone (B).61
The usual dose of testosterone gel determined physiological levels of serum testosterone at physiological levels that were not significantly changed after association
of any dose of oral testosterone (B).62
Therefore, the comparative analysis between the main
types of ART has shown that all are safe, and transdermal
forms and TUD are the most physiological.
Recommendation
The comparative analysis between the main types of ART
has shown that all are safe, and transdermal forms and
TUD are the most physiological. The use of TUD or testosterone gel is recommended, whenever possible, for ART
in hypogonadal patients.
What is the role of prolonged action
testosterone?
There are two formulations of long acting testosterone undecanoate, one presented in 750 mg vials, available in the
US, and another with 1000 mg vials, available in Europe and
South America. Both are well tolerated by patients, are able
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Martits AM et al.
to maintain physiological and stable levels of serum testosterone and DHT (B)59 and have similar effectiveness and safety as other injectable forms (B)58,63 (D).64 The advantage of
TUD is that with only 4-5 injections per year testosterone
levels can be maintained at physiological levels (B).15
TUD appears to have a role in the treatment of metabolic syndrome. A follow-up of patients with metabolic syndrome and ADAM using TUD for a period of one
year showed that testosterone levels were restored to the
normal average value. There was a significant improvement in sexual symptoms, metabolic syndrome parameters and body composition. There was no change in PSA,
blood glucose and liver function, and the levels of hemoglobin and hematocrit did not exceed the upper limit of
a normal range (A)36 (B)38 (C).16
The increase in blood pressure, hematocrit > 50% and
worsening lipid profile that may occur in a small number
of patients were related to the number of CAG repeats of
the androgen receptor and the presence of obesity (B).57
ART with long acting TU proved to be safe for a period
of 24 months of treatment.
Recommendation
The main role of long acting testosterone is maintenance of
physiological serum testosterone levels with a lower number
of applications and consequently lower rate of side effects.
Is there a difference in absorption
between the many pharmacological
preparations?
Each formulation has a distinct characteristic, depending
on the presentation, dose and pharmacokinetics. The testosterone esters used in short acting injectable formulations are derived from fatty acids and depend on the esters being releases from the oily vehicle and the
hydrolysis of these esters in order to release of testosterone into the circulation. The pharmacokinetics are determined in part by the size of the side chain, hence the
wide variation in the use of different esters modulates the
level of circulating testosterone (D).41
The testosterone levels obtained with short acting injectable forms are unstable (B),55,61 whereas long acting
injectable forms provide more stable levels.
In the oral formulations, absorption is variable and
bioavailability is generally poor due to the effect of first
passing through the liver. Oral testosterone undecanoate
is preferentially absorbed by chylomicrons, avoiding the
liver. However, the testosterone level is sub-optimal and
it must be taken various times per day (D).41
The oral mucosa patches and sublingual formulation are not often used. The first seems to have a good
absorption similar to that of gels, but a shorter half-life, requiring use twice per day (B).43 Transdermal patches are presented in formulations that vary in size and
thus the dose of testosterone. Studies indicate that absorption is efficient and reaches equilibrium in 48 hours
(B).44 The absorption of scrotal patches is more efficient
because the skin is thinner and increased production of
DHT occurs because the amount of 5 alpha reductase
in that region is higher (D).41 The evening application
of the patch produces serum testosterone mimicking
the circadian rhythm of healthy men, while the application of the gel in the morning produces physiological
and stable serum testosterone levels (B),15,46,55,61 which
shows the different absorption mechanisms between
the two formulations.
Recommendation
The differences in absorption between the various pharmaceutical forms depend on the presentation, dose and
pharmacokinetics. Testosterone levels obtained by short
acting injectable forms and oral forms are more unstable
and less physiological. On the other hand, the levels obtained by means of injection and for long acting transdermal forms are stable and physiological. The only pharmaceutical form that mimics the circadian rhythm is that
of scrotal patch. The preferential use of the long acting
injectable form or transdermal forms is recommended
for ART.
What are the contraindications for
ART?
An increased risk of cardiovascular events has been observed in elderly patients with ADAM associated with
other chronic diseases.
The administration of testosterone is contraindicated in men with prostate or breast cancer, in men with
palpable prostate nodules or PSA greater than 4 ng/mL
or 3 ng/mL in high risk patients (D).41,48
ART is recommended to be applied with caution in
men with benign prostate hypertrophy and mild or moderate urinary symptoms, while men with severe urinary
symptoms should undergo urologic evaluation before
starting treatment.
Testosterone should not be used in men with hematocrit > 50% or patients with grade III or IV CHF. Men
with moderate or severe obstructive sleep apnea should
be evaluated by a specialist before starting ART (D).48
Recommendation
There are few studies with high levels of evidence in relation to the contraindications of testosterone replacement.
It is weakly recommendable to not use testosterone in patients with prostate or breast cancer with PSA > 4 ng/mL
or 3 ng/mL in high risk patients or those with palpable
prostate nodule, hematocrit greater than 50% or in patients with grade II or IV CHF.
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comparison of a novel testosterone bioadhesivebuccal system, striant, with
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Image in medicine
Spontaneous rupture of renal pelvis secondary to ureteral obstruction by urothelial tumor
Spontaneous rupture of renal pelvis secondary to ureteral
obstruction by urothelial tumor
Ruptura espontânea de pelve renal secundária à obstrução ureteral por tumor urotelial
Daniel Alvarenga Fernandes1*, Ana Laura Gatti Palma2, Ricardo Yoshio Zanetti Kido2, Ricardo Hoelz de Oliveira Barros1,
Daniel Lahan Martins3, Thiago José Penachim3, Nelson Marcio Gomes Caserta4
Radiologist, Assistant Physician, Department of Radiology, Faculty of Medical Sciences – State University of Campinas (FCM-Unicamp), Campinas, SP, Brazil.
Resident Physician, Department of Radiology, FCM-Unicamp, Campinas, SP, Brazil.
3
Radiologist, Assistant Physician, Department of Radiology, FCM-Unicamp; Radiological Center of Campinas – Hospital Vera Cruz; Pontifical Catholic University of Campinas (PUCC), Campinas, SP, Brazil.
4
PhD-Professor, Department of Radiology, FCM-Unicamp, Campinas, SP, Brazil.
1
2
Study conducted at the Department of Radiology, Faculty of Medical Sciences –
State University of Campinas (FCM-Unicamp), Campinas, SP, Brazil.
Article received: 10/6/2013
Accepted for publication: 2/20/2014
*Correspondence:
Address: Department of Radiology of Faculty of Medical Sciences – State University of Campinas (FCM-Unicamp), Campinas, SP, Brazil.
Rua Tessália Vieira de Camargo, 126, Cidade Universitária “Zeferino Vaz”.
Campinas, SP – Brazil
[email protected]
[email protected]
http://dx.doi.org/10.1590/1806-9282.60.05.006
Conflict of interest: none
Introduction
Case report
Partial spontaneous rupture of the upper urinary tract is
rare and usually associated with nephrolithiasis. Other reported causes, apart from instrumentation and trauma,
involve obstructive ureteral tumor in the pelvic cavity, retroperitoneal fibrosis, fluid overload, and pregnancy. We
report a case of spontaneous rupture of renal pelvis secondary to ureteral obstruction caused by urothelial tumor,
clinically suspected and evaluated by CT scans and MRIs,
discussing the relevant findings for diagnosis.
Male patient, 55 years, with a clinical picture of macroscopic hematuria and insidious lower back pain similar to
cramps for about six months, which became stronger in
recent months. The patient reports a fever, not measured.
Denies trauma, previous surgery, history of urolithiasis,
other complaints, and past illnesses. Former smoker (22
packs/year, having quit smoking for eight years). On physical examination, the patient showed good general health,
being thin (body mass index of 17.2 Kg/m2), pallid (1+/4),
A
Figures 1A and 1B Computed tomography, contrast-enhanced axial sections; excretory phase shows irregular parietal thickening of the left
B
ureteropelvic junction, causing ureteral obstruction (black arrow) and moderate upstream pyelocaliceal dilatation (dashed arrow). Rupture of the renal
pelvis with contrast extravasation and formation of posterior perirenal urinoma is also observed (white arrow).
415
Fernandes DA et al.
A
B
C
D
Figures 2A, 2B, 2C and 2D MRI with T2-weighted images, coronal (2A) and axial (2B), three-dimensional MR urography (2C) and
post-contrast T1 image (2D) revealing vascularized tumoral thickening of the proximal left ureter (black arrow), causing ureteral obstruction and
moderate pyelocaliceal upstream dilation (dashed arrow). Associated rupture of the renal pelvis with contrast extravasation and formation of
posterior perirenal urinoma also observed (white arrow), displacing the kidney anterolaterally.
hypohydrated (2+/4), acyanotic, anicteric, eupneic and
afebrile. Abdomen with bowel sounds present and preserved, slightly painful on palpation in the left flank and
iliac fossa. Painful lumbar fist percussion on the left.
Based on the clinical picture, we requested a contrasted
multi-slice computed tomography (Figures 1A and 1B) and
subsequent complementation with MR urography - Uro-MRI (Figures 2A, 2B, 2C and 2D). Vascularized tumoral thickening of the proximal left ureter evident, causing ureteral
obstruction and moderate pyelocaliceal upstream dilation.
Associated rupture of the renal pelvis with contrast extravasation and formation of posterior perirenal urinoma is also
observed, displacing the kidney anterolaterally.
Imaging diagnosis (with subsequent histopathological confirmation) led to the conclusion that it was a case of spon-
taneous rupture of renal pelvis and formation of urinoma
secondary to ureteral obstruction due to urothelial tumor.
Discussion
In the case described, the spontaneous rupture of renal
pelvis was caused by urothelial tumor. The rupture diagnosis can be clinically suspected and confirmed by imaging. The clinical picture includes macro or microscopic
hematuria (75%), back pain (18%), dysuria (6%) and less
frequently palpable mass, decreased appetite, weight loss,
and may sometimes be asymptomatic.1-4
Urothelial tumors can affect any part of the urinary
tract is relatively rare in the upper urinary tract (approximately 1% of all urothelial tumors), most frequently affecting patients in the sixth and seventh decades of life. The
Spontaneous rupture of renal pelvis secondary to ureteral obstruction by urothelial tumor
histological subtypes include transitional cell carcinoma
(TCC) (90%), squamous cell carcinoma (9%), mucinous
adenocarcinoma (less than 1%), sarcomas, undifferentiated tumors and benign tumors (mesodermal inverted papilloma, and fibroepithelial polyp). Risk factors involve
smoking, prolonged exposure to dyes such as aniline, petrochemical agents and tar, analgesic abuse (especially phenacetin), Balkan nephropathy, as well as factors that promote urinary stasis, as horseshoe kidneys. The use of
cyclophosphamide, in turn, increases the risk of high-grade urothelial tumors. Chronic infection and calculi may
also be associated with squamous cell carcinoma and mucinous adenocarcinoma. Schistosomiasis can be associated with the squamous cell carcinoma, and also seems to
be associated with a greater degree of epigenetic changes
in the epithelium of the genitourinary tract.4-6
There is a clear need in patients with upper urinary tract
tumors for imaging investigation of the entire urinary tract,
due to possible synchronous bladder cancer in 2-4% of patients. Furthermore, the need for follow-up is well established, as 40-50% of patients with TCC will develop metachronous tumours involving the lower urinary tract.3-5
Urotomography (Uro-CT) performed with equipment
with multiple rows of detectors (MDCT) is being increasingly used for evaluation of synchronous and metachronous tumors in the upper urinary tract and primary
evaluation of hematuria. Imaging studies are also used
to differentiate tumors and benign urothelial changes
which might not require additional invasive assessment
such as ureteroscopy and retrograde pyelography.7-9 The
differential diagnosis of tumors in the upper urinary tract
includes nephrolithiasis, blood clot, infection, tuberculosis, ectopic papilla, endometriosis and malakoplakia.
Factors that help to reach a correct diagnosis include
knowledge of the location, lesion density and pattern of
impregnation, pericalicinal/periureteral opacification associated or not, and multiplicity of lesions. In the unenhanced phase of Uro-CT, TCCs are discreetly hyperdense compared to urine (15-30HU), unlike clots and stones
(with respective densities at 40-80 HU and above 200HU).
Since most of them are hypovascularized, they are discreetly impregnated by contrast (increase of 40-70HU),
and to a lesser intensity than normal renal parenchyma,
appearing in the excretory phase of the examination as
fixed filling defects.5 In addition to technological improvements in MDCT, refinements in the tests’ radiological
orientation have probably contributed to increase the capacity to detect urothelial abnormalities. Different techniques have been used, such as abdominal compression,
administration of intravenous saline solution, diuretics
or both, “log-rolling” (asking patients to roll 360º) prior
to excretory phase to maximize opacification and distention of the urinary tract.
On MRI, TCCs can appear hypointense or isointense
compared to the renal parenchyma on T1- and T2-weighted sequences, making it necessary to use paramagnetic
contrast agents in non-dilated urinary tract, being the TCCs
less contrasted than the renal parenchyma. In patients with
impaired renal function, static MR urography can help detect tumors of the upper urinary tract, especially in obstructed kidneys, since TCCs are usually hypointense compared to urine on T2-weighted images, which facilitates
their detection when associated to hydronephrosis. The
use of diffusion-weighted imaging (DWI) sequences associated with conventional T1- and T2-weighted sequences
increases the accuracy and sensitivity of Uro-MRI.10,11
Conclusion
Although rare, spontaneous rupture of renal pelvis secondary to ureteral obstruction caused by urothelial tumor
may be suspected clinically, and the detailed radiological
analysis of tomographic images and MRI-guided sequences, including Uro-MRI, is of great importance for both
diagnosis and follow-up of these patients.
References
1. Tripathi S, Ahmad A, Mathew VV. Spontaneous partial rupture of the upper
renal tract. Case Report. Brunei Int Med J. 2011; 7 (4): 215-219.
2. Ashebu SD, Elshebiny YH, Dahniya MH. Spontaneous rupture of the renal
pelvis. Australas Radiol. 2000; 44:125-7.
3. Kaplan M, Aktoz T, Atakan IH. A rare cause of acute flank pain: spontaneous
rupture of the renal pelvis. Turkish Journal of Urology 2009; 35(3):256-259.
4. Inahara M, Kojima S, Takei K, Naito H, Kito H, Yamazaki K, et al. Two cases
of spontaneous rupture of upper urinary tract caused by the primary ureteral
or renal pelvic tumor: a case report. Acta Urologica Japonica. 2009; 55(1):
31-34.
5. Prando A. Tumores uroteliais. In: Muller CIS, D’Ippolito Giuseppe, Rocha
AJ, series editors. Prando A, Baroni RH, associated editors. Urinário (Colégio
Brasileiro de Radiology and Diagnostic Imaging; 5). Rio de Janeiro: Elsevier;
2013. p. 321-358.
6. Gutiérrez MI, Siraj AK, Khaled H, Koon N, El-Rifai W, Bhatia K. CpG island
methylation in Schistosoma- and non-Schistosoma-associated bladder
cancer. Modern Pathology (2004) 17, 1268–1274.
7. Silverman SG, Leyendecker JR, Amis ES. What is the current role of CT
urography and MR urography in the evaluation of the urinary tract?
Radiology 2009; 250:309–323.
8. Dillman JR, Caoili EM, Cohan RH, Ellis JH, Francis IR, Schipper MJ. Detection
of upper tract urothelial neoplasms: sensitivity of axial, coronal reformatted,
and curved-planar reformatted image-types utilizing 16-row multi-detector
CT urography. Abdom Imaging 2008; 33:707–716.
9. Sadow CA, Wheeler SC, Kim J, Ohno-Machado L, Silverman SG. Positive
Predictive Value of CT Urography in the Evaluation of Upper Tract Urothelial
Cancer. AJR 2010; 195:337–343.
10. Yoshida S, Masuda H, Ishii C, Tanaka H, Fujii Y, Kawakami S, et al. Usefulness
of Diffusion-Weighted MRI in Diagnosis of Upper Urinary Tract Cancer.
AJR 2011; 196:110–116.
11. Padhani AR, Liu G, Koh DM, Chenevert TL, Thoeny HC, Takanara T, et al.
Diffusion-weigheted magnetic resonance imaging as a cancer biomarker:
consensus and recommendations. Neoplasia 2009; 11:102-125. 417
at bedside
Bernardo LS et al.
Estresse em enfermeiros de unidades de terapia intensiva
Rosemeire de Jesus Ferreira Leitão1, Janayna Thainá Rabelato2, Wanderley Marques Bernardo3
Coordinator of the nursing program at the Lusíada University Center – UNILUS.
1
2
Medicine Undergraduate Student at the Lusíada University Center – UNILUS.
3
PhD-Professor at the do Lusíada University Center – UNILUS.
http://dx.doi.org/10.1590/1806-9282.60.05.007
Objective
To assess the level of stress, and associated activities in
nurses working in the Intensive Care Unit.
Methods
Prospective cross-sectional study to answer the following
questions: is the stress level of nurses working in ICU
high? Is there a relationship between stress and working
conditions? Which of the activities of nurses generate
more stress?
The population consisted of 71 nurses working in ICUs,
distributed in 6 hospitals. Data collection was performed
using the Bianchi questionnaire,1 based on the 51-item total stress score for nurses, including the relationship with
other units and superiors (A), activities related to the unit’s
proper functioning (B), staff administration (C), nursing
care provided to the patient (D), unit coordination (E) and
working conditions (F). The total score value has a variation of 51 points (when the nurse classifies all activities as
stressful) and 357 points (when the nurse classifies all activities as very stressful), resulting in the average value
between 1 and 7. Levels obtained were classified into low
(equal to or less than 3), moderate (3.1 to 5.9) and high
(equal to or greater than 6) levels of stress.
Results
Regarding general data, the majority were female (74.64%),
aged 31-40 years (46.67%), married (53.5%), with children
(59.15%). 61.97% of these nurses do not have another job
and 60.56% work 12-hour shifts. Regarding training time,
38.02% had work experience of two to five years and 84.5%
of respondents had graduate degree diplomas.
The average stress of these nurses reached a score of
3.87, which according to the reference values is equivalent to a moderate stress level. The highest stress score
was 4.27, and the lowest stress score of 3.36. There was
no significant difference between hospitals (p = 0.65).
In terms of score distribution among hospitals, 49 nurses (69.01%) show moderate levels, 20 nurses (28.16%) have
low levels, and 2 nurses (2.81%) have high levels of stress.
There was no significant difference in the level of
stress in relation to gender, age, dual employment, working hours, training time and graduate degree.
Regarding domains, personnel administration (C)
showed a higher stress score. Performing activities with
minimal time available was the most stressful activity (F).
Nursing care provided to the patient (D) showed a higher
number of stress-generating activities.
Conclusion
Regardless of the results of this study, it is important to
establish parameters to systematically measure the stress
level of health professionals involved in care or administrative activities. The stress level of nurses in this study
or in other samples may indicate specific areas to receive
interventions aiming at improving performance and quality of patient care.
Reference
1. Bianchi ERF. Escala Bianchi de stress. Revista da Escola Paulista, São Paulo,
v. 43, p.1055 - 1062, 2009.
418Rev Assoc Med Bras 2014; 60(5):418
original article
Stephani Felício da Silva Campi1, Luiz Fernando C. Nascimento1*
Department of Medicine. University of Taubaté, Taubaté, SP, Brazil
1
Summary
Study conducted at the University of
Taubaté, Taubaté, Brazil
*Correspondence:
Address: Av. Tiradentes, 500 –
Bom Conselho
Taubaté, SP – Brazil
Phone: +55 12 3625-4271
Fax: +55 12 3621-8796
[email protected]
http://dx.doi.org/10.1590/1806-9282.60.05.008
Objective: to identify spacial patterns for cesarean deliveries per microregion in
the state of São Paulo.
Methods: this is an ecological and exploratory study with data on live births occurred between 2003 and 2007 in 63 microregions in the state of São Paulo. Variables analyzed included cesarean delivery rates, teenage mothers, mothers with
high levels of education and who had at least seven prenatal consultations.
Moran’s index (I), a measure of spatial autocorrelation of rates related to the variables described above and which identifies the presence of spatial clusters, was
calculated. The distributions of the variables’ rates in this study were visualized
using thematic maps. The Moran map was used to identify microregions with
high priority need for attention. Pearson correlation coefficients among the variables were also obtained.
Results: there were 3,045,293 births, being 1,636,009 (53.7 %) cesarean deliveries.
It was possible to identify spatial clusters of C-sections (I = 0.58 and p < 0.01) in
the microregions located on the north and northwest of the state of São Paulo,
as well as in Guaratinguetá; the values found for Moran index were, I = 0.32,
I = 0.30 and I = 0.24, for the rates of teenage mothers, schooling and number of
consultations, respectively, being all significant results (p <0.01). Micro-regions
with high-priority need for attention were identified. Cesarean rates were significantly correlated with high rates of maternal education and number of prenatal consultations.
Conclusion: the identification of these microregion clusters with high rates of
cesarean delivery allows health managers to implement policies in order to minimize these rates.
Keywords: spatial distribution of the population, public health, C-section, maternal age, maternal education, geographic information systems.
Introduction
Currently, Brazil has an overall C-section rate of 32%, reaching 90% in some private clinics.1 In the state of São Paulo,
the rate of C-sections amounts to 32.9% in the public setting and 80.4% in private setting.2 Compared to spontaneous vaginal delivery, cesarean section is associated with an
increased risk of infections, occasional need for blood transfusion, pneumonia, cardiopulmonary complications,
thromboembolism and gastrointestinal disorders in women giving birth.1, 3 - 6 In addition, the risk of hospital readmission within sixty days after surgery is higher than that
seen after spontaneous vaginal delivery.5
A recent review showed that the rates of cesarean delivery have increased in recent years in European countries, and the rates around the world have been between
13.5% and 39.2% of births.7
Geoprocessing is becoming an important tool in the
field of Public Health, as it allows an overview of a particular problem. This technique was used in determining areas for malaria control,8 in the spread of the AIDS epidemic,9 and in the study of birth profiles in Vale do Paraíba.10
One of its applications encompasses the identification of spatial clusters defined as any cluster of events
419
Campi SFS et al.
that is not merely casual and whose identification is the
focus of research in spatial statistics.
With the development of these maps, we seek to examine whether the distribution of these events actually follows a pattern in terms of space or if it is a random event.
The objective of this study was to identify spatial clusters of cesarean section rates in microregions of the state
of São Paulo.
Methods
This is a study of ecological and exploratory design, in which
secondary data from live births were used; the information
was gathered from the Datasus portal and refers to microregions within the state of São Paulo in the period from January 1, 2003 to December 31, 2007. Data were georeferenced
according to the place of residence of the mother. These data
were analyzed using TerraView 4.0.0. software program, made
available by the National Institute for Space Research - INPE
(www.dpi.inpe.br/terraview/). The proportions of cesarean
deliveries were calculated according to the following groups:
mothers aged below 20 years, mothers with formal education above eight years (high school and above), and mothers who had seven or more prenatal consultations. These
proportions were obtained in percentages and compared to
the total number of live births.
63 microregions that make up the state of São Paulo and have an approximate population of 41 million inhabitants were analyzed.
The spatial statistics used a georeferenced database
of the microregions, and a data analysis technique divided by area in order to obtain the Global Moran’s index
(I). The equation that expresses this index takes into account the number of areas (microregions), the weights of
the neighborhoods, the average incidence rate of cesarean section for each microregion in the periods studied
and the mean values for the entire study area.
The Moran’s index is a global measure of spatial autocorrelation; spatial autocorrelation measures the association of values of a single variable Y within any specific area i with the values of the same variable Y, however
measured for an area neighboring i. That is, the index
measures the extent to which the value of a variable in an
area is associated with the same variable in neighboring
areas. We can say that autocorrelation measures the level of spatial interdependence between the variables and
the strength of the relation determining whether that is
a random distribution or not. Its value is contained in
the [-1; 1] interval. The closer to 1, the more similar the
areas compared to each other, whereas the closer to –1,
the least similar these areas would be from each other.
These indices were calculated for all areas. Thematic
maps that allow visual identification of the distribution
of these events in the microregions were prepared.
A Moran map of C-section rates was created; the map
shows areas of high priority for possible intervention. The
Moran map is a two-dimensional representation of the
Moran scatterplot where each polygon is displayed, indicating its quadrant in the scattering diagram. In this map,
the microregions located in Q1 require special attention
in order to reduce the rates of the studied outcome, which
in our case is the rate of cesarean deliveries.
The Pearson correlation coefficients between C-section rates and other variables were estimated.
Tables with the coefficients of global Moran and Pearson correlation were built. The variables were expressed
as percentages in the tables, with mean, minimum and
maximum values.
As this is an ecological study using secondary data
obtained from the network, identifying the subject is not
possible, and thus approval by the Research Ethics Committee was not required.
Results
During the study period, there were 3,045,293 live births,
of which 1,636,009 (53.7%) were delivered by cesarean section. The percentages of other variables, along with their
mean, minimum and maximum values are shown in Table 1. The high mean value of the proportion of cesarean deliveries is clearly observed.
Table 1 Mean, minimum and maximum (Min – Max)
values, and respective standard deviations (SD) of rates
per 100 live births, delivered by C-section; mothers with
high level of education; mothers aged less than 20 years
(adolescents); and mothers who had seven or more
prenatal consultations, by microregion in the state of São
Paulo, from 2003 to 2007
Mean (SD)
Min- Max
Cesarean delivery
57.0 (10.8)
31.7 – 76.8
Adolescent mothers
19.5 (2.3)
14.6 – 25.0
Mothers with high level of education 70.8 (7.5)
42.4 – 72.8
Mothers who had seven or more
39.4 – 93.7
74.1 (10.2)
prenatal consultations
The Moran index (I) was positive and significant for all
variables studied, demonstrating the presence of spatial
clusters for all determinants.
The spatial distribution of cesarean deliveries, represented here by rates per 100 live births, by microregion
in the state of São Paulo, from 2003 to 2007, is shown in
Figure 1. The presence of high rates of cesarean sections
in the north and northwest part of the state is evident,
with spatial clusters toward the border of the states of
Minas Gerais, Mato Grosso do Sul and northern Paraná,
as well as in the microregion of Guaratinguetá, within
Vale do Paraíba. Lower rates were found to the south of
the state near the border of Paraná and in the microregions of Avaré, Franco da Rocha, and Campos do Jordão.
Moran’s index was I = 0.58 (p< 0.01).
31.73
43.01
54.28
65.56
0
NS
High
Low
43.01
54.28
65.56
78.84
100
with higher proportions of mothers who had at least 7
consultations in the microregions located in the central,
northern and northwestern parts of the state. The lowest
proportions are seen in a strip of 12 microregions stretching from east, in the border of the state of Rio de Janeiro,
all the way to the state of Paraná, including the Greater
São Paulo metropolitan area.
The Moran map for C-section rates is shown in Figure 2 and indicates an area of high priority for intervention in 13 microregions located in the north and northwest of the state, close to the border of the states of Minas
Gerais and Mato Grosso do Sul.
N
200
N
0
100
200
300
km
km
Figure 1 Spatial distribution of rates of cesarean delivery, in
Figure 2 Microregions of the state of São Paulo according to
percentages, by microregion in the state of São Paulo, 2003-2007.
priority – high, low and non-significant (NS) – for intervention in rates
of cesarean delivery. Microregions in the state of São Paulo, 2003-
The spatial distribution of the proportion of teenage mothers, by microregion, identified larger proportions in the
southern part of the state, in the microregions of Avaré,
Itapeva, Capão Bonito, and Registro, close to the border
of Paraná, in addition to Ituverava, which is located upstate. Lower rates are located east of the state, in the microregions of Amparo, Campinas, Jundiaí, Osasco, São
Paulo, Guarulhos, and São José dos Campos, as well as
in Franca and Ribeirão Preto, upstate. Moran’s index was
I = 0.32 ( p < 0.01). The distribution of these microregions
is similar to that observed for cesarean rates.
The spatial distribution for maternal schooling above
eight years of formal education by microregion found higher proportions in the west of the state, bordering the north
of the state of Paraná, and in Vale do Paraíba. Moran’s index for this variable was I = 0.30 (p < 0.01). The spatial distribution of this variable’s proportions in the microregions
is similar to that of the proportions of cesarean sections.
Regarding the number of medical consultations, the
Moran index was positive and significant (I = 0.24; p<0.01),
2007.
cesarean rates were negatively correlated, although not
significantly, with the rates of teenage mothers (r = -0.14);
in contrast, the correlations with educational level (r =
0.50) and number of consultations (r = 0.60) were statistically significant.
Discussion
The importance of this study is to identify spatial clusters of microregions with high rates of cesarean delivery.
These clusters of micro-regions with high rates of cesarean sections are located in the north and northwest of
the state of São Paulo. This is, to our knowledge, the first
study using this type of approach.
The data obtained from Datasus refer to all deliveries including those conducted by the Federal Unified
Health System (SUS) or private institutions (covered by
health plans and pregnant women who receive care in private clinics).
421
Campi SFS et al.
According to the Ministry of Health, C-sections already represent 43% of the deliveries carried out in Brazil both in public and private settings, while the World
Health Organization recommends that C-sections are
performed in no more than 15% of births, always in situations that involve risks for both mother and child.11 A
study by Barros et al.,11 conducted in the city of Pelotas
(state of Rio Grande do Sul) in 2004 showed an overall
cesarean rate of 45%, being 36% performed in patients assisted by the SUS and 81% in the private setting, where
35% of C-sections performed electively. When taking into
account private health plans, it appears that this percentage is even higher, reaching 80%.12
In the public SUS setting, however, C-sections account for 26% of all births. According to the Interagency
Health Information Network (RIPSA, in Portuguese) report in Brazil, from 2008, cesarean deliveries are more
common among women with higher levels of education,
reaching almost 70% among those with 12 years or more
of schooling and being less 20% among women with less
formal education. The mother’s education variable can
be treated as an approximation of maternal social class
and remains as the most important factor associated with
birth weight and neonatal mortality. A study by Freitas
et al.13 showed that women over age 30 have a higher probability of cesarean delivery than women below 20 years.
Comparing the spatial distribution of cesarean births
and mothers under age 20, a higher rate of teenage mothers was observed in areas to the south of the state, where
fewer cesarean deliveries are performed, suggesting that
microregions with lower socioeconomic development are
those with the highest rates of teenage mothers and lower rates of cesarean section. Likewise, Simões et al.14 analyzed characteristics of adolescent pregnancy in São Luís,
Maranhão, and observed that the general characteristics
of adolescent mothers differed from older women. In the
study presented here, the highest rates of adolescent mothers are concentrated in rural areas with possible compromised infrastructure.
The geographical distribution of the percentages of
mothers with more than eight years of education shows
a pattern with lower values in
the microregions of Registro, Capão Bonito, Piedade, and Paraibuna/Paraitinga,
indicating that areas with worst infrastructure are those
with higher proportions of mothers with low education
and lower rates of cesarean delivery. Similarly, a study by
Haidar et al.,15 conducted in Vale do Paraíba, found that
maternal education is strongly associated with type of delivery when mothers with higher levels of education have
a six times greater chance of having their children by cesarean section. This seems to be due to the mother’s choice,
as much as their physician’s. Since cesarean sections are
usually more expensive procedures, mothers with higher
levels of education and consequently better economic
conditions, may opt for it.
This statement must be viewed with caution because
some microregions may present lower C-section rates due
to areas with worst socioeconomic conditions, where birth
care can be precarious to the point of compromising the
outcomes of both mother and child.
The spatial patterns for cesarean section according
to maternal age and education found in this study were
similar to those found by D’Orsi and Carvalho.16
After spatial analysis of the distribution of mothers
who had at least 7 prenatal consultations, it is clear that
the microregions with the highest rates are concentrated
in the central, northern and northwestern parts of the
state, and these also have higher C-section rates; the Pearson correlation coefficient showed a strong correlation
between this variable and cesarean deliveries; the spatial
distribution of rates of mothers who had at least seven
prenatal consultations reached a significant value for the
Moran index. This spatial distribution is similar to that
of mothers with high levels of education, suggesting that
they initiate prenatal care earlier, possibly, and have more
contact with the obstetrician, which facilitates the choice
for cesarean delivery.13 We must remember that a greater
number of prenatal consultations can be a sign of a risky
pregnancy, which in turn may require cesarean delivery.
As seen in the Moran map, 13 microregions were found
as high priority for intervention in order to reduce the
rates of cesarean deliveries in northern and northwestern
areas of the state, close to the border of Minas Gerais and
Mato Grosso do Sul; it is noteworthy that these are microregions with the highest rates of highly educated mothers. Possibly, in regions where coverage of health plans is
greater, cesarean rates also tend to be higher.
This study may have limitations, some related to the
status of ecological study and other related to the data.
The source of the research - Datasus - is widely used in
ecological studies but may not have offered socioeconomic information, or information about the type of complications occurred in both vaginal and cesarean deliveries.
The impact of cesarean section on the health of the newborn was not mentioned, either; causal relationships cannot be identified, but possible associations can be suggested. Furthermore, neonatal deaths that could be
associated with type of delivery were not analyzed.
Conclusion
The identification of these microregion clusters with high
rates of cesarean delivery, as well as the identification of
microregions with high priority for intervention allows
health managers to implement measures in order to minimize these rates.
Resumo
Distribuição espacial das cesarianas no Estado de São
Paulo.
Objetivo: identificar padrões espaciais para partos cesarianos por microrregião do Estado de São Paulo.
Métodos: estudo ecológico e exploratório com dados de
nascidos vivos entre 2003 e 2007 de 63 microrregiões do
Estado de São Paulo. As variáveis analisadas neste estudo foram, além de taxas de parto cesariano, taxas de mães
adolescentes, de mães com alta escolaridade e de mães
que realizaram pelo menos 7 consultas no pré-natal. Foram calculados os índices de Moran (I), que estimam autocorrelação espacial das taxas das variáveis acima descritas e identificam a presença de aglomerados espaciais.
Essas taxas foram visualizadas pelos mapas temáticos;
microrregiões com alta prioridade de atenção foram identificadas pelo mapa de Moran. Foram calculados os coeficientes de correlação de Pearson entre as variáveis.
Resultados: houve 3.045.293 partos, sendo 1.636.009
(53,72%) partos cesarianos. Foi possível identificar aglomerados espaciais de cesarianas (I = 0,58 e p < 0,01) nas microrregiões ao norte e noroeste do Estado, além de Guaratinguetá. Os valores dos índices de Moran foram, para as
taxas de mães adolescentes, I = 0,32; para as taxas de alta
escolaridade, I = 0,30; e para as taxas do número de consultas, I = 0,24, todos significativos (p<0,01). Foram identificadas microrregiões com alta prioridade de intervenção.
As taxas de cesarianas estiveram correlacionadas significativamente com as taxas de alta escolaridade materna e com
número de consultas.
Conclusão: a identificação desses aglomerados de microrregiões com altas taxas de cesarianas permite aos gestores
de saúde implantar políticas para minimizar tais taxas.
Palavras-chave: distribuição espacial da população; saúde pública; cesariana; idade materna; escolaridade materna; sistemas de informação geográfica.
References
1. Villar J, Valladares E, Wojdyla D, Zavaleta N, Carroli G, Velazco A, et al. WHO
2005 global survey on maternal and perinatal health research group.
Caesarean delivery rates and pregnancy outcomes: the 2005 WHO global
survey on maternal and perinatal health in Latin America. Lancet.
2006;367:1819-940.
2. Kilsztajn S, Carmo M, Machado Jr L, Lopes E, Lima L. Caesarean sections
and maternal mortality in São Paulo. Eur J Obstet Gynecol Reprod Biol.
2007;132:64-9.
3. Burrows LJ, Meyn LA, Weber AM. Maternal morbidity associated with vaginal
versus cesarean delivery. Am J Obstet Gynecol. 2004;103:907-12.
4. Golfier F, Vaudoyer F, Ecochard R, Champion F, Audra P, Raudrant D.
Planned vaginal delivery versus elective caesarean section in singleton term
breech presentation: a study of 1116 cases. Eur J Obstet Gynecol Reprod
Biol. 2001;98:186-92.
5. Liu S, Heaman M, Joseph KS, Liston RM, Huang L, Sauve R, et al. Risk of
maternal postpartum readmission associated with mode of delivery. Am J
Obstet Gynecol. 2005;105:836-42.
6. Martins-Costa, SH, Ramos JGL, Serrano YLG. Trauma during pregnancy.
Rev. Bras. Ginecol. Obstet. 2005;27:505-8.
7. Patah LEM, Malik AM. Modelos de assistência ao parto e taxa de cesárea
em diferentes países. Rev Saúde Pública. 2011;45:185-94.
8. Rodrigues AF, Escobar AL Souza-Santos R. Análise espacial e determinação
de áreas para o controle da malária no Estado de Rondônia Rev Soc Bras
Med Trop. 2008;41:55-64.
9. Szwarcwald CL, Bastos FIP, Esteves MAP, Andrade CLT. A disseminação da
epidemia da AIDS no Brasil, no período de 1987-1996: uma análise espacial.
Cad Saúde Pública. 2000;16(Supl 1):S07-S19.
10. Hau LC, Nascimento LFC, Tomazini JE. Geoprocessamento para identificar
padrões do perfil de nascimentos na região do Vale do Paraíba. Rev Bras
Ginecol Obstet. 2009;31:171-6.
11. Barros AJD, Santos IS, Matijasevich A, Domingues MR, Silveira M, Barros FC,
Victora CG. Patterns of deliveries in a Brazilian birth cohort: almost universal
cesarean sections for the better-off. Rev Saúde Pública. 2011;45:635-43.
12. Almeida S, Bettiol H, Barbieri MA, Silva AAM, Ribeiro VS. Significant
differences in cesarean section rates between a private and a public hospital
in Brazil. Cad Saúde Pública. 2008;24:2909-18.
13. Freitas PF, Sakae TM, Jacomino MEMLP. Medical and non-medical factors
associated with cesarean section rates in a university hospital in southern
Brazil. Cad Saúde Pública. 2008;24:1051-61.
14. Simões VMF, Moura da Silva AA, Bettiol H, Lamy-Filho F, Tonial R, Mochel
EG. Características da gravidez na adolescência em São Luís, Maranhão. Rev
Saúde Pública. 2003;37:559-65.
15. Haidar FH, Oliveira UF, Nascimento LFC. Escolaridade materna: correlação
com os indicadores obstétricos. Cad Saúde Pública. 2001;17:1025-9.
16. D’Orsi E, Carvalho, MS. Perfil de nascimentos no Município do Rio de
Janeiro: uma análise espacial. Cad Saúde Pública. 1998;14:367-79.
423
original article
Santos APT et al.
Ana Paula de Torres Santos1,2, José Eduardo Levi3, Marcílio Figueiredo Lemos1, Samira Julien Calux1, Isabel Takano Oba1,
Regina Célia Moreira1*
Center for Blood and Sexually Transmitted Diseases, Adolfo Lutz Institute, São Paulo, SP, Brazil
1
Laboratory of Immunology of the Central Laboratory Department at Hospital das Clínicas, Faculty of Medicine, University of São Paulo (USP), São Paulo, SP, Brazil
2
Virology Laboratory of the Institute of Tropical Medicine, USP, São Paulo, SP, Brazil
3
Summary
Study conducted at the Adolfo Lutz
Institute, São Paulo, SP, Brazil
*Correspondence:
Instituto Adolfo Lutz
Address: Av. Dr. Arnaldo, 355
São Paulo, SP – Brazil
[email protected]
Objective: the aim of this study was to identify HBV genotypes in serum samples from patients from the state of São Paulo, received by the viral hepatitis laboratory, at the Virology Centre of Instituto Adolfo Lutz, from various municipalities.
Methods: a total of 94 serum samples were randomly analyzed. Genotyping was
performed using nested PCR for amplification of S and Pol regions from viral
genome. Genotypes were identified comparing the sequences obtained with the
sequences deposited in GenBank.
Results: we were able to determine the genotype of 91 (97%) samples, as follows:
genotype A (55.3%), D (32%), F (5.3%), C (3.2%) and G (1%). There are few data
on the epidemiology of genotype G. This genotype has been detected in restricted areas around the world. Frequently, the genotype G infection occurs in HIV-positive male patients. In our case, the sample identified as G was also positive
for HIV but in a female patient, which is an uncommon finding in the scientific
literature.
Conclusion: in this work, we identified the most frequent genotypes in São Paulo as well as the genotype G, rare among the genotypes found in our environment.
http://dx.doi.org/10.1590/1806-9282.60.05.009
Keywords: hepatitis B, polymerase chain reaction, genotype, Brazil.
Introduction
Hepatitis caused by the hepatitis B virus (HBV) is a disease of great importance to public health around the world.
Approximately 30% of the world’s population, or about
2 billion people, have serologic evidence of current or past
infection with HBV. Of these, it is estimated that approximately 360 million people are chronically infected and
600,000 die every year due to acute severe hepatitis, hepatocellular carcinoma or cirrhosis.1
HBV has ten distinct genotypes (A to J), identified
and defined according to a difference of 8% in their genomic sequences. Recent studies suggest that HBV genotypes may differentially affect the severity of liver diseases such as cirrhosis and hepatocellular carcinoma, as
well as response to treatment.2 The HBV genotypes have
distinct geographical distribution. Genotype A is found
mainly in North America and Africa. Genotypes B and C
are prevalent in Southeast Asia and the Far East, and the
latter has been associated with increased risk of hepatocellular carcinoma. Genotype D has been found throughout the world with the highest prevalence in the
Mediterranean, Middle East, South Asia and particularly
in India. Genotypes E and F are prevalent in West Africa
and Brazil’s indigenous population, respectively. Moreover, genotype G has been reported in the USA, France, Colombia and Brazil while genotype H has been found in
North and Central America. Recently, through phylogenetic analysis, a new genotype was characterized in Vietnam and Laos, being designated as genotype I,3,4 while
genotype J was identified in Japan.5 In Brazil, the most
common genotype is A, followed by genotypes D and F.
The North, Northeast and Southeast regions have a higher
frequency of genotype A, while genotype D is the most
common in the South.6 In some regions, genotypes B and
C are also detected at low prevalence, reflecting the presence of descendants of Asian immigrants in these populations.7 A study conducted in Ribeirão Preto, São Paulo,
found genotype D in 56.5% of the cases, genotype A in
41.3%, and genotype in 2.2%.8 The presence of these genotypes reflects the mix of cultures in Brazil: Native American, European and African backgrounds make the
country an important model for studies of population
genetics, suggesting an influence of the immigration pattern in each region.9
The aim of this study was to identify HBV genotypes
in samples received by the viral hepatitis at the Adolfo
Lutz Institute, for determining HBV viral load.
Terminator V.3.0 kit. The genotypes were confirmed using
the genotyping tool available from the NCBI website
(http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.cgi).
Results
Of all the samples analyzed, 50 were from females and 44
from male patients, ages ranged from 1 to 71 years with
a median of 40 years. All 94 samples extracted and analyzed by PCR tested positive. Through sequencing, we were
able to determine the genotypes of 91 samples (97%) (Figure 1) and genotypes were: A (55.3%), D (32%), F (5.3%),
C (3.2%) and G (1%). To confirm the sample identified as
genotype G, another extraction, PCR and sequencing were
performed.
5 1 3
Methods
Sampling
During this study, samples from chronic carriers of HBV
patients, treated by Public Health Services in the state of
São Paulo, were analyzed in order to initiate or monitor
treatment. Clinical follow-up and laboratory diagnosis
of these patients were performed using commercial tests
available throughout Brazil, approved and regulated by
the National Health Surveillance Agency (Anvisa) of the
Ministry of Health.
The sample consisted of 94 plasma specimens from
patients from health centers and public hospitals in the
state of São Paulo, in the period comprising June 2010
to May 2011. The samples were stored in a freezer at -20°C
and thawed immediately before testing.
DNA extraction
Extraction of HBV DNA was carried out using the commercial kit QIAamp® DNA Mini and Blood Mini Handbook - QIAGEN®, as described in the manufacturer’s instructions.6
Polymerase chain reaction
The polymerase chain reaction (PCR) was performed as
described by Kaneko et al.10,11 with some modifications.
The S and Pol regions were amplified according to the
protocol reported by Sitnik et al.,7 for subsequent identification of the HBV genotypes.
Sequencing
To determine the genotypes, we used the product amplified by Nested-PCR of S and Pol regions of HBV. The positive samples were sequenced using ABI Prism BigDyeTM
Genotype A
30
52
3
Genotype C
Genotype D
Genotype F
Genotype G
Not genotyped
Figure 1 Distribution of the HBV genotypes identified in samples
collected in the state of São Paulo.2
Discussion
HBV genotyping may be an important tool for prognosis
of disease progression and treatment. Furthermore, it may
be important for understanding the evolution and epidemiology of the virus, since the genotypes vary according
to geographic region and often correlated with risk factors.
As expected, the most prevalent genotypes in the study
population were genotypes A and D, and these results are
consistent with studies on the prevalence of genotypes in
Brazil. Genotypes A and D are the most prevalent worldwide, while genotype F is prevalent in the Americas and
genotype C is characteristic of the Asian population; genotype C is also quite common in the state of São Paulo.
Compri et al.12 found genotypes A, D and C in children,
adolescents and their families in the state of São Paulo.
Moraes et al.13 found genotypes A, D and F in Rio de Janeiro. These same genotypes were also described in populations in Goiânia and Santa Catarina.14,15,16
Recent studies have suggested that the rate of lamivudine resistance was higher in patients infected with HBV ge425
Santos APT et al.
notype A than those with genotype D.17,18 Genotype C has
been associated with lower rates of spontaneous clearance
of HBeAg in serum compared to infection with genotype B.
In addition, genotype C is associated with higher levels of
HBV DNA replication, more advanced liver disease, hepatocellular carcinoma, and a decreased rate of response to interferon treatment compared with genotype B.19
A strain of genotype G, which is not common in our
population, was also identified in this study. The genotype G sample came from a female patient carrying the
human immunodeficiency virus (HIV). Bottecchia et al.20
identified the genotype G in a patient infected with HBV
and in only two patients coinfected with HIV. The presence of genotype G has been associated with sexual relations between men.21 A study conducted by Sanchez et
al.22 showed a high prevalence of genotype G only in men
who have sex with men (MSM) and always coinfected with
another genotype of HBV. In Brazil, Silva et al.23 identified two patients with genotype G in this population
which could somehow be associated with this sexual behavior.
Genotype G was first described in 2000.24 Later, this
genotype was also identified in the United States, Canada, Brazil, Mexico, France, Germany, Vietnam, Thailand,
and Japan.21,25,26 Genotype G is essentially identical to the
other HBV genotypes, but has some unique features including an insertion of 36 bp at the gene start codon.24
Genotype G is the rarest of all HBV genotypes. This genotype is usually found as a coinfection with other HBV
genotypes.26 Work conducted by Bottecchia et al.20 demonstrated that patients with HBV genotype G presented lamivudine-resistance mutations and large genetic
variation among samples, which points out the importance of the circulation of genotype G in Brazil for the
treatment of HBV. Nevertheless, epidemiological and clinical data are still limited, probably due to the low incidence worldwide.
Among the approximately 40 million people infected
with HIV worldwide, an estimated two million to four
million are also chronically infected with HBV.27 The prevalence rates of HIV/HBV coinfection, obtained in Brazilian studies of samples from health services, are between
5.3% and 24.3%. The increased incidence of chronic complications of viral hepatitis in this population has been
observed, which differs from what is seen with other opportunistic diseases. This is explained by increased survival of HIV-infected patients from the use of antiretrovirals. In general, HBV infection tends to be more
aggressive in HIV-infected individuals than in mono-infected patients, with highest rates of HBV carriers, higher
HBV viremia levels, more frequent episodes of activation
and more rapid progression to cirrhosis.27
The identification and determination of epidemiology
and molecular characteristics of circulating HBV genotypes is important and can be a tool for prognosis and treatment of HBV as well as the hepatitis C virus (HCV). Furthermore, it demonstrates the circulation of different viral
strains in Brazil. Clinical follow-up of individuals with chronic HBV infection should be one of the concerns, making it necessary to implement continuous measures of
prevention-based health education. The most effective measure to combat HBV infection is active immunization of
susceptible individuals, using currently available vaccines,
which are highly efficient and safe, in addition to encouraging the use of condoms, and spreading information on
the risk presented by manicures and drug users. These measures enable the creation of programs for infection control, seeking eventual eradication of hepatitis B and prophylaxis of hepatocellular carcinoma.28
Conclusion
In this study, we identify the HBV genotypes prevalent in
the state of São Paulo. Genotypes identified are those already described in previous studies, and we also found a
sample infected with genotype G, a rare genotype, associated with men who have sex with other men, HIV-positive. However, in our study, genotype G was found in a
female HIV-infected patient, which demonstrates the relevance and need of genotyping a larger number of patients. Genotyping is an important tool for prognosis of
disease progression, treatment, and better understanding
of the virus’ evolution and epidemiology, since genotypes vary according to geographical regions and often correlate with risk factors.
Project approved on 9/29/2009 by the Research Ethics
Committee of the Adolfo Lutz Institute – CEPIAL (CCD-BM 06/2009), according to Resolution 196/96 on research
involving human subjects, published by the National
Health Council – Ministry of Health – Brasília (1996).
Project no 09/53086-4 2, financed by the FAPESP.
Resumo
Identificação dos genótipos do vírus da hepatite B no Estado de São Paulo.
Objetivo: o objetivo deste estudo foi identificar os genótipos
do HBV nas amostras de soros recebidas pelo Laboratório de
Hepatites do Centro de Virologia do Instituto Adolfo Lutz.
Métodos: foram analisadas aleatoriamente 94 amostras
de soropositivas, provenientes de diversos municípios do
Estado de São Paulo. Para determinação dos genótipos, foi
realizada Nested-PCR das regiões S e Pol do HBV. Os genótipos foram identificados comparando os resultados
amplificados com as sequências depositadas no GenBank.
Resultados: foi possível determinar o genótipo de 91 (97%)
amostras do total analisado e os genótipos identificados
foram: genótipos A (55,3%), D (32%), F (5,3%), C (3,2%) e
G (1%). Há poucos dados a respeito da epidemiologia do
genótipo G. Esse genótipo tem sido detectado em áreas
restritas do mundo. Geralmente, a infecção pelo genótipo
G ocorre em indivíduos HIV positivos do sexo masculino.
Neste trabalho, a amostra identificada como G foi também
positiva para HIV e era de uma paciente do sexo feminino,
dado raro na literatura científica.
Conclusão: neste trabalho, foram identificados os genótipos mais frequentes, assim como uma cepa do genótipo
G, rara entre os encontrados em nosso meio.
Palavras-chave: hepatite B; reação em cadeia da polimerase; genótipo; Brasil.
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HC, et al. Hepatitis B virus genotypes circulating in Brazil: molecular
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SS, et al. Distribution of hepatitis B virus genotypes and viral load levels in
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detection of serum hepatitis B virus DNA using the polymerase chain
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al. Detection of serum hepatitis B virus DNA in patients with chronic
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12. Compri AP, Miura I, Porta G, Lemos MF, Saraceni CP, Moreira RC. Hepatitis
B virus infection in children, adolescents, and their relatives: genotype
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13. Moraes MT, Gomes AS, Niel C. Sequence analysis of the pre-S/S gene of
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14. Teles SA, Martins RM, Vanderborght B, Stuyer L, Gaspar AM, Yoshida CF.
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427
original article
Ferreira S et al.
Silvia Ferreira1, Margarida Ferreira2*, Alice Carvalhais3, Paula Clara Santos4, Paula Rocha5, Gabriela Brochado6
Visiting Professor, Department of Physiotherapy, North Polytechnic Institute of Health, CESPU-Gandra (Portugal).
1
PhD student at the Research Centre in Physical Activity, Health and Leisure, Faculty of Sport, University of Porto (Portugal); Visiting Professor, Department of Physiotherapy, North Polytechnic Institute of Health,
2
CESPU-Gandra (Portugal).
Associate Professor, Department of Physiotherapy, North Polytechnic Institute of Health, CESPU-Gandra (Portugal).
3
Associate Professor, Department of Physiotherapy, School of Health Technology of Porto, Institute Polytechnic of Porto (Portugal).
4
Associate Professor, Department of Physiotherapy, North Polytechnic Institute of Health, CESPU-Gandra (Portugal).
5
Coordinated and associate professor, Department of Physiotherapy, North Polytechnic Institute of Health, CESPU-Gandra (Portugal).
6
Summary
*Correspondence:
Centro Hospitalar do Alto Ave
Address: Rua dos Cutileiros,
Medicina Física e Reabilitação
Guimarães – Portugal
[email protected]
Objective: to verify the effectiveness of the pelvic floor muscles rehabilitation
program (PFMRP) in female volleyball athletes, analyzing the amount and frequency of urinary leakage.
Methods: experimental study. The sample consisted of 32 female athletes from
Famalicão Athletic Volleyball Club (Portugal). The athletes were selected by convenience and distributed randomly into two groups: experimental group (EG =
16 athletes) and the control group (CG = 16 athletes). The EG underwent PFMRP
for three months. The PFMRP was the awareness and identification of the pelvic floor muscles (PFM), pre-timed PFM contraction prior to occasions of increased intra-abdominal pressure, and 30 daily contractions of MPP at home.
The CG had only access to the pamphlet. The assessment instruments included
the questionnaires, the Pad Test (amount of urinary leakage) and frequency record of urinary leakage (7-day diary) before and after PFMRP.
Results: the amount of urine leakage decreased in 45.5% of athletes under PFMRP
intervention, and in 4.9% of athletes in CG, with statistical differences between
the groups (p < 0.001). The reduction in the frequency of urinary leakage was
14.3% in EG, and 0.05% in CG, a statistically significant difference between the
groups (p < 0.001).
Conclusion: PFMRP in this study was effective to reduce stress urinary incontinence in female volleyball athletes. The program allowed significant improvement of symptoms of quantity and frequency of urinary leakage.
http://dx.doi.org/10.1590/1806-9282.60.05.010
Keywords: sports athletes, stress urinary incontinence, physical therapy.
Introduction
There is a general consensus among authors that despite the distinct benefits of sport in young athletes, such as
improved cardiovascular and respiratory systems, the reduction of adipocytes, increased endurance, muscular hypertrophy and increased strength, and higher bone density, adversely urogynecologic problems arising from
physical activity may occur, including amenorrhea, oligomenorrhea, short phase of the corpus luteum, anovulation and urinary incontinence.1
In the last decade, several studies have demonstrated
and reflected the association between urinary incontinence (UI) and high-impact sports.1,2
Epidemiological studies related pregnancy and childbirth as probable primary etiologic factors of stress uri-
nary incontinence (SUI). In fact, the prevalence of SUI is
higher in multiparous women than in nulliparous.3 However, a recent study of SUI in young nulliparous athletes showed a prevalence of 36.4%.4
Some studies have shown that the high prevalence of
SUI in nulliparous athletes is associated with the type of
sport. A systematic review conducted in 2004,2 revealed
that the prevalence of UI during sports practice varied
between 0% (golf) and 80% (trampoline).
Modalities that include activities such as jumping and
running seem to have an increased risk of triggering urinary leakage in athletes, due to sudden increase in intra-abdominal pressure.5 Hay6 noted that the impact on the
pelvic floor while running is three to four times the body
weight, five to twelve times while jumping, nine times in
the case of pole vault, and more than nine times in the
practice of high jump. The sudden increase in intra-abdominal pressure associated with sports and abdominal and
pelvic muscle imbalance is the main risk factor for SUI in
young nulliparous athletes.7 Some theories based on risk
factors have been developed to explain the occurrence of
UI in young nulliparous athletes. The muscle dysfunction
in pelvic floor associated with the stretching of the pubocervical fascia results in hypermobility of the bladder neck.
This dysfunction is triggered by the action of jumping,
which causes direct injury to the structures of the pelvic
floor. The fatigue of the Pelvic Floor Muscles (PFM) caused by high repetition of running and jumping activities
results in decreased blood flow to the muscle fibers with
depletion of nutrients and oxygen.2,8
The pelvic floor muscles rehabilitation programs
(PFMRP) are currently the first-line intervention in the
treatment of SUI in women with incontinence and associated risk factors.9 These PFMRP include different treatment approaches such as biofeedback, electrical stimulation, manual strengthening techniques, vaginal cones
and exercises to strengthen the pelvic floor muscles
(PFM).9,10 PFMRPs that only include teaching proper PFM
contraction, awareness of pelvic floor in the body function, and functional interaction between PFM and the
muscles forming the abdominal wall have shown cure rates from 56 to 70% in women with urinary incontinence
and associated risk factors.10 Investigations showed a reduction in the frequency and amount of UI episodes and
increased strength of PFM in 6 to 12 weeks.10-12
The relevance of this study lies in the lack of randomized controlled studies in athletes, the lack of awareness among health professionals, coaches and athletes
for the prevention and treatment of UI. Therefore, the
aim of this investigation was to verify the effectiveness of
a program of rehabilitation of the pelvic floor muscles
(PFMRP) in federated nulliparous athletes.
Methods
The study is experimental in nature, and the initial sample consisted of sixty-six female athletes from Famalicão
Athletic Volleyball Club (Figure 1). The final sample consisted of thirty-two athletes with symptoms of stress urinary incontinence, randomly divided in two groups: experimental group and control group, both with sixteen
athletes (Figure 1). A lottery design was used for randomization of the sample, i.e., 32 folded pieces of paper were
placed in a common box, so that 16 were assigned the
number 1 (control group) and the remaining were marked as number 2 (experimental group). Each athlete wiRev Assoc Med Bras 2014; 60(5):428-433
thdrew from the box a single piece of paper, without
knowledge of the meaning of that number, which ensured blinding of participants.
Initial sample
(n=66)
Excluded athletes (n=34)
- Continents
age> 30 years
- Pad-test ≤1g
Randomized sample
(n=32)
Experimental group
(n=16)
Control group
(n=16)
Figure 1 Sample selection.
Sample selection began in the last week of December 2011,
using a baseline questionnaire and pad-test. Inclusion criteria included nulliparous female volleyball athletes, symptoms of stress UI, age between 13 and 30 years, and amount
of urinary leakage greater than 1 g. Exclusion criteria were
treatment for less than six months, sport practice for less
than two years, repeated urinary infections or at the time of
sample selection, body mass index below 18 kg/m2 or above 25 kg/m2, and PFMRP adherence under 50%.
The study was previously approved by the president
of the club, and informed consent given by either the athletes or their legal guardians.
In the last week of December 2011, both groups underwent a baseline questionnaire, pad test and assessment
of frequency of urinary leakage (urinary diary). Three
months after introduction of PFMRP, in the first week of
May 2012, the groups were once again assessed through
a final questionnaire (attached), pad test and frequency
of urinary leakage. The frequency of UI episodes consisted of a daily log of urinary leakage for seven consecutive days.13 The amount of urinary leakage was assessed by
pad test, in the first 15 minutes of volleyball practice.14 A
preweighed sanitary pad branded Carefree Essentialstm
was properly placed before training. After 15 minutes of
physical activity, the pad was removed and weighed on a
Kenwood Ds700 digital scale. Athletes were considered
incontinent with losses exceeding one gram.15
EG underwent PFMRP, which initially consisted of
educational action, awareness of PFM and receipt of the
information pamphlet. CG only had access to the pamphlet, which displayed a summary of the educational action.
The educational action included teaching of the anatomy and physiology of the lower urinary tract, concepts
of UI and SUI, etiology of SUI in athletes, preventive strategies for urinary leakage, exercise-related disorders in
athletes, location of the PF muscles, identification and
429
Ferreira S et al.
awareness of correct contraction of PFM, types of PFM
contraction, Knack technique and knowledge of PFM exercises to be performed at home.
The educational action also included a urinary diary for
EG. The urinary diary consisted of daily records of the
amount of liquid intake, urinary frequency and volume for
three consecutive days. The urinary diary enabled an improved perception of the changes in everyday life behavior and
hygiene. The PFM exercises that the athletes would be required to perform at home included 30 sustained contractions and four quick contractions after each sustained contraction, in different positions and daily for three months.
Weekly visits were made at the club during the study
period to ensure motivation and adherence to PFMRP in
EG both at home and after the training sessions.
Normality of variables was assessed in the statistical
analysis with the nonparametric test of Shapiro-Wilk,
and the Student t-test was applied for independent
and paired samples. At the intersection of variables,
the Chi-square test was used. Whenever the applicability conditions were not met, we used the Fisher’s
alternative exact test. All data were collected and analyzed using SPSS, version 20.0, with a significance level of 5%.
Results
The characterization of the sample groups revealed no
statistically significant differences in all parameters.
The groups are homogeneous and can be compared
(Table 1).
Table 1 Sample characterization of the experimental group (EG) and control group (CG)
EG (n = 16)
CG (n = 16)
x ±SD (min-max)
x ±SD (min-max)
p+
19.4 ± 3.24 (16-25)
19.1 ± 2.11 (17-26)
0.749
22.8 ± 2.57 (19.2-24.9)
2.4 ± 1.67 (1-4)
21.5 ± 1.81 (19.2-24.1)
1.6 ± 0.72 (1-6)
0.135
0.064
4.9 ± 2.51 (3-15)
4.8 ± 0.61 (3-6)
0.106
0.745
Demographics
Age (years)
BMI (kg/m2)
Duration of UI (years)
Characteristics of the sport
Sports practice (years)
6.9 ± 4.09 (2-12)
Weekly training sessions (number)
3.6 ± 0.93 (3-6)
Characterization of SUI
Frequency of leakage
n (%)
Once or several times in a month
5 (31.3%)
Once or several times in a week
11 (68.8%)
Amount of urinary leakage
Drops
7 (43.8%)
Small amount (weak stream of urine)
9 (56.3)
Severity of UI
Low
1 (6.2%)
Moderate
10 (62.5%)
High
5 (31.2%)
Triggering activities
Training
14 (87.5%)
Competition
2 (12.5%)
Activities of daily life
Yes
3 (37.5%)
No
13 (62.5%)
Prevention strategies for urinary leakage sanitary pads (during sports)
Yes
11 (68.8%)
No
Bathroom (prior to sports)
Yes
No
Reducing the amount of liquid intake (prior to sports)
Yes
No
n (%)
8 (50%)
8 (50%)
6 (37.5%)
10 (62.5%)
0.113#
0.685#
5 (31.2%)
5 (31.2%)
6 (37.5%)
0.109#
13 (81.3%)
3 (18.8%)
1.000*
6 (37.5%)
10 (62.5%)
0.433*
11 (68.8%)
1.000#
5 (31.2%)
5 (31.2%)
14 (87.5%)
2 (12.5%)
16 (100%)
0 (0.00%)
0.484*
9 (56.3%)
7 (43.8%)
8 (50.0%)
8 (50.0%)
0.723#
x ±SD= mean and standard deviation.
T-Student test for two independent samples.
Chi-squared test.
*Fisher’s exact test.
+
#
The variation of the initial and final mean values showed

a statistically significant decrease in the amount of urinary leakage in EG, while in CG no significant differences were seen at the end of the study. In EG, the mean value fell 45.5% while in CG, the decrease reached 4.9%, which
represents a significant difference between the groups
(Table 2).
Table 2 Intra- and inter-group comparison of the
variation in amount of urinary leakage
EG (n = 16)
x ±SD
CG (n = 16)
p
x ±SD
(min-max)
Pad-test
(-) 2 ±1.28
variation
(1-4.5)
p
(min-max)
<0.001*
(-) 0.2 ± 0.41
0.324
(0.3-1.2)
<0.001+
(Final-initial)
x ±SD= mean and standard deviation.
*p<0.05 intra-group.
+
p<0.05 inter-group.
The variation between the initial and final mean value for
frequency of UI episodes was statistically significant in
EG (Table 3).
In terms of variation of mean values, there was significant reduction in the frequency of UI episodes in 14.3%
of the subjects in EG, and in 0.05% of the women in CG.
This decrease in variation in UI episodes was significant
between the groups (Table 3).
Table 3 Intra- and inter-group comparison of the
variation in the frequency of incontinence episodes
EG (n=16)
x ±SD
(min-max)
CG (n=16)
p
x ±SD
p
(min-max)
Variation of FIE
(-) 0.3 ± 0.50 <0.001* (-) 0.1 ± 0.44
(Final-initial)
(0-2)
(0-3)
0.414
<0.001+
X±SD=mean and standard deviation; FIE=frequency of incontinence episodes.
*p<0.05 intra-group.
+
p<0.05 inter-group.
Discussion
The importance of sports for women’s general health, the
increasing need for knowledge about the effects of high
impact sports activities on lower urinary tract and the
evidence of treatment of UI in nulliparous athletes have
recently fueled scientific research in this area.2,16
In the present study, the characterization of the total sample revealed a mean age of 19 years. According to
a study by BØ & Borgen,8 the prevalence of urinary leakage in female athletes occurs between 15 and 39 years
old.
In the analysis of BMI, the athletes’ total mean was
22 Kg/m2, considered by the National Health Nutrition
Examination Survey as normal weight. In the study by
BØ & Borgen,8 the mean BMI of the athletes was also one
of normal body weight, which is consistent with the results obtained in the present study. Waldrop17 reported
that metabolic and hormonal changes in athletes can result in UI. Hormonal deficits (hypoestrogenism) reduce
blood flow in arteriovenous plexus, mucosal coaptation,
and urethral pressure, promoting IU.17,18
In this study, the parameters of frequency and amount
of urinary leakage were used to determine the degree of
UI, showing a greater percentage of athletes with moderate severity. Roza et al.20 found mild and moderate UI in
sports such as track and field, basketball, volleyball and
handball. The severity of UI increases with the type and
the continuity of high-impact sports (running, jumping),
with equally progressive consequences both for sports
performance and the quality of life of female athletes. In
the present study, none of the athletes resorted to a doctor for early intervention and to prevent worsening of the
condition. Thyssen et al.,16 in a sample of young dance
athletes, showed that only 3.3% told a doctor about the
symptoms of urinary incontinence.
In this study, the highest percentage of urinary leakage was triggered during training, 87.5% in EG and 81.3%
in CG. These results are in agreement with the study by
Thyssen et al.,16 who demonstrated that athletes who practice sports such as gymnastics, basketball, volleyball and
handball had 95.2% of urinary leakage during training
against 51.2% during competitions. This aspect can be
explained by the high level of catecholamines in stress situations, such as in competitions.16
The present study demonstrated that athletes of both
groups resorted to strategies or measures to prevent urinary leakage. In decreasing order, the measure most commonly used to conceal urinary leakage was the use of a
sanitary pad, followed by bladder emptying and the reduction of fluid intake before training. Eliasson et al.20
found the same strategies in a sample of 18 gymnastics
athletes.
In this study’s baseline assessment, the groups showed no significant differences regarding the amount of
urinary leakage (pad-test). After three months of PFMRP,
EG reduced significantly the occurrence of urinary leakage, down 45.5% compared with 4.9% in CG, statistically
significant differences being found between the groups.
431
Ferreira S et al.
The baseline mean value found for amount of urinary leakage in this study was 4.4 g. In a study published
by Eliasson et al.,20 which included a sample of 18 gymnastics athletes, the average amount of urinary leakage
was 28 g (9-56 g). This difference can be explained by the
type of sport, since gymnastics presents more impact than
volleyball.2,16
Regarding the frequency of urinary leakage, baseline
assessment showed an average frequency of 2.1 episodes
in seven days, falling to 1.8 (14.3%) episodes in EG and
1.9 (0.05%) in CG by the end of the study period. By the
end of the study, GE significantly decreased the frequency
of urinary leakage compared to CG (p < 0,001).
A single study was published, including a small sample of volleyball players, with a combined treatment program (biofeedback, electrical stimulation, PFM strengthening exercises and vaginal cones). And after 4 months of
intervention, the results showed that the program was
effective in reducing the use of sanitary pads and symptoms of urinary leakage during volleyball training and
activities of daily life.21
MPP no domicílio. O GC teve acesso unicamente ao panfleto. Os instrumentos de avaliação englobaram os questionários, o pad-test (quantidade de perda urinária) e o registro da frequência das perdas urinárias (diário de 7 dias),
antes e após o PRMPP.
Resultados: a quantidade de perda urinária diminuiu
45,5% no GE, com intervenção do PRMPP, e 4,9% nas atletas do GC, verificando-se diferenças estatisticamente significativas entre os grupos (p<0,001). Na frequência das
perdas urinárias, a redução foi de 14,3% no GE e de 0,05%
no GC, verificando-se diferenças estatisticamente significativas entre os grupos (p<0,001).
Conclusão: o PRMPP, nessa amostra, foi eficaz na incontinência urinária de esforço em atletas do sexo feminino
de voleibol, pois permitiu melhorar significativamente os
sintomas de quantidade e frequência das perdas urinárias.
Conclusion
1. Warren M, Shanta, S. The female athlete. Bailliere’s Clin Endocrinol Metab.
2000;14(1):37-53.
2. BØ K. Urinary Incontinence, Pélvic Floor Dysfunction, Exercise and Sport.
Sports Med. 2004;34(7):451-64.
3. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The
standardisation of terminology of lower urinary tract function: Report from
the standardisation sub-committee of the International Continence Society.
Neurourol Urodyn. 2002;21(1):167-78.
4. Jácome C, Oliveira D, Marques DA, Sá-Couto. Prevalence and impact of
urinary incontinence among female athletes. Int J Gynaecol Obstet.
2011;114(1):60-3.
5. Peschers UM, Voudusek DB, Fanger G, Schaer GN, DeLancey JO, Schuessler
B. Pelvic muscle activity in nulliparous volunteers. Neurourol Urodyn.
2001;20(3):269-75.
6. Hay JG. Citius, altius, longius (faster, higher, longer): the biomechanics of
jumping for distance. J Biomech 1993;26(Suppl 1):7-21.
7. BØ K. Pressure measurements during pelvic floor muscle contractions: the
effect of different positions of the vaginal measuring device. Neurourol
Urodyn. 1992;11(1):107-13.
8. BØ K, Borgen JS. Prevalence of stress and urge urinary incontinence in elite
athletes and controls. Med Sci Sports Exerc. 2001;33(11):1797-802.
9. Dumoulin C, Hay-Smith J. Pelvic floor muscle training versus no treatment,
or inactive control treatments, for urinary incontinence in women. Cochrane
Database Syst Rev. 2010:20(1):CD005654.
10. Hay-Smith EJ, Dumoulin C. Pelvic floor muscle training versus no treatment,
or inactive control treatments, for urinary incontinence in women. Cochrane
Database Syst Rev. 2006;25(1): CD005654.
11. Konstantinidou E, Apostolidis A, Kondelidis N, Tsimtsiou Z, Hatzichristou
D, Ioannides E. Short-term efficacy of group pelvic floor training under
intensive supervision versus unsupervised home training for female stress
urinary incontinence: a randomized pilot study. Neurourol Urodyn.
2007;26(4):486-91.
12. Subak LL, Quesenberry CP, Posner SF, Cattolica E, Soghikian K. The Effect
of Behavioral Therapy on Urinary Incontinence: a randomized controlled
trial. Obstet Gynecol. 2002;100(1):72-8.
13. Lose G, Fantl JA, Victor A, Walter S, Wells TL, Wyman J, et al. Outcome
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dysfunction. Neurourol Urodyn. 2001;17(3):255-62.
14. Hahn I, Fall M. Objective quantification of stress urinary incontinence: a short,
reproducible, provocative pad-test. Neurourol Urodyn. 1991;10(5):475-81.
This study leads to the conclusion that the program of
rehabilitation of pelvic floor muscles in this sample was
effective for the reduction of stress urinary incontinence
in volleyball athletes. The program of rehabilitation of
the pelvic floor muscles allowed a significant improvement of clinical symptoms in the amount and frequency
of urinary leakage.
Resumo
Reeducação dos músculos do pavimento pélvico em atletas de voleibol.
Objetivo: verificar a eficácia do programa de reeducação
dos músculos do pavimento pélvico (PRMPP) em atletas
femininas de voleibol, analisando a quantidade e a frequência das perdas urinárias.
Métodos: estudo experimental. A amostra foi constituída por 32 atletas do sexo feminino do Atlético Voleibol
Clube de Famalicão (Portugal). As atletas foram selecionadas por conveniência e distribuídas aleatoriamente em
dois grupos: o grupo experimental (GE = 16 atletas) e o
grupo-controle (GC = 16 atletas). O GE foi submetido ao
PRMPP durante 3 meses; o programa consistiu na conscientização e identificação dos músculos do pavimento
pélvico (MPP), na pré-contração dos MPP ao aumento da
pressão intra-abdominal, e em 30 contrações diárias dos
Palavras-chave: atletas desportivas, incontinência urinária de esforço, fisioterapia.
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433
original article
Campolina AG et al.
Expansion of morbidity: trends in healthy life expectancy of the
elderly population
Alessandro Gonçalves Campolina1*, Fernando Adami2, Jair Licio Ferreira Santos3, Maria Lucia Lebrão4
Center for Translational Research in Oncology, Institute of Cancer of São Paulo, Faculty of Medicine, University of São Paulo (FMUSP), Brazil.
1
Department of Collective Health. ABC Medical School. Santo André, SP, Brazil.
2
Department of Social Medicine. Medicine School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
3
Department of Epidemiology. Faculty of Public Health, University of São Paulo, São Paulo, SP, Brazil.
4
Summary
Study conducted at the Faculty of Public
Health, University of São Paulo, São Paulo,
SP, Brazil
*Correspondence:
Address: Av. Dr. Arnaldo, 251, 8o andar
Cerqueira César
Phone: +55 11 3893-3550
Fax: +55 11 3893-3024
[email protected]
Objective: to analyze the changes in life expectancy (LE) and disability-free life
expectancy (DFLE) in São Paulo’s elderly population to assess the occurrence of
compression or expansion of morbidity, between 2000 and 2010.
Methods: cross-sectional and population survey, based on official data for the
city of São Paulo, Brazil, and data obtained from the Health, Well-Being and
Aging Survey (SABE). Functional disability was defined as difficulty in performing at least one basic activity of daily living. The Sullivan method was used to
calculate LE and DFLE for the years 2000 to 2010.
Results: from 2000 to 2010, there was an increase in disabled life expectancy
(DLE) in all age groups and both sexes. The proportion of years of life free of disability, at 60 years of age, decreased from 57.94% to 46.23% in women, and from
75.34% to 63.65% in men. At 75 years of age, this ratio decreased from 47.55% to
34.54% in women, and from 61.31% to 56.01% in men.
Conclusion: the expansion of morbidity is an ongoing process in the elderly population of the municipality of São Paulo, in the period of 2000-2010. These results can contribute to the development of preventive strategies and planning
of adequate health services to future generations of seniors.
http://dx.doi.org/10.1590/1806-9282.60.05.011
Keywords: life expectancy, active life expectancy, life tables, morbidity, elderly.
Introduction
Brazil is a country that has had one of the fastest population aging processes in recent times. The proportion of
elderly (aged ≥ 60 years) increased from 4.6% in 1950 to
8.7% in 2010.1 In 2050, Brazil will be one of six countries
with the highest proportion of elderly individuals (approximately 60 million).1
As aging is associated with increased prevalence of
chronic diseases, it is essential to investigate under what
conditions the years gained with increased life expectancy
of the Brazilian population will be lived, in order to contribute to the knowledge of the needs of the elderly and
provide data for the allocation of health resources and
planning of public policies.2
Therefore, three hypotheses were formulated in order
to discuss the effect of changing patterns of morbidity and
mortality in the health status of the populations.3,4
The first hypothesis is known as the compression of
morbidity, and suggests that life expectancy has reached
adult biological limits. As a result, if the incidence of di-
sabling diseases can be extended, morbidity will then be
compressed to a shorter period of time.5,6
The second hypothesis proposes that the decline in
mortality derives from a reduction in the case fatality rates of diseases and not from reductions in their incidence or progression. Thus, the decline in mortality is accompanied by an increase in the number of people with
chronic disease and disability.7
The third hypothesis states that the decline in mortality is partly due to the decline in disease lethality, but
at the same time the incidence and progression of chronic diseases should fall, leading to a dynamic equilibrium.
According to this idea, the years with severe morbidity
and disability remain relatively constant, since medical
interventions and changes in lifestyle reduce the rate of
progression of chronic diseases.8
The concept of healthy life expectancy, proposed in
the 1960s9 and developed in the 1970s,10 refers to the average number of years of life that people of a certain age
can expect to live healthy11 and can be used to assess the
occurrence of compression of morbidity in a population.12
Indicators of healthy life expectancy, such as disability-free life expectancy (DFLE), can provide information not
only on the prevalence of functional disability, but also
on the potential duration of disability and the time during which a given population will need health care.13
In Brazil, a few studies have evaluated the healthy life
expectancy of the general population and the elderly population. In 2005, Romero and colleagues evaluated the
healthy life expectancy of the population, based on information obtained from the database of the Brazilian Census Bureau (IBGE), using two approaches: one from the
self-assessment of health status and the other based on
the self-assessment of limitations in activities of daily living. The authors showed that both approaches showed
very similar estimates, particularly in populations with
older age and the proportion of lost years of healthy life
is more important in women.14
Also in 2005, Camargo and colleagues used a database of 2000 belonging to the Health, Well-Being and Aging
(SABE) survey and, by assessing the life expectancy with
functional disability in elderly individuals in São Paulo,
they showed that, although older women in this city presented higher life expectancy compared to men, the proportion of years lived free of disability was lower.15
In 2009, Camargos and colleagues, using the self-perception of health status, categorized into good or bad, as
a measure of health status in older individuals using information obtained from the National Survey by Household Sampling (PNAD) of 2003, estimated a healthy life
expectancy for the Brazilian population aged 60 years and
older. The estimates also revealed that women live longer,
but the number of years they live with a perception of poor
health is greater than the estimate for older men.16
In 2011, another study based on the SABE survey and
which used longitudinal data reinforced the stronger impact of disability in females, evidenced by the higher life
expectancy of women with disabilities.17
Given that in the Brazilian context the time trends
of healthy life expectancy in the elderly population haven’t
been evaluated yet, indicators such as disability-free life
expectancy (DFLE) may provide key information for the
planning of health care in this population.
The aim of this study is to analyze the changes in life
expectancy and disability-free life expectancy in elderly
individuals living in São Paulo, from 2000 to 2010, based on the SABE survey, in order to evaluate the occurrence of compression or expansion morbidity in this population.
Methods
Study design and sampling
Repeated cross-sectional study using data from SABE survey - Health, Well-Being and Aging, which constitutes a
population-based survey aimed to assess the living conditions of the elderly in seven cities of Latin America and
the Caribbean (Argentina, Barbados, Brazil, Chile, Cuba,
Mexico and Uruguay).18
In Brazil, the SABE survey was initiated in 2000 in
São Paulo’s metropolitan area, including 2143 elderly
individuals aged 60 years or older of both genders. The
sampling was random and representative of the elderly
population in São Paulo in 1996, which totaled 836,223.19
The sample was initially composed of 1568 individuals,
being extended to 2143 in order to increase the number
of male seniors aged 75 years or older, due to the higher
mortality rate in this age group and gender.20 To obtain
the desired number of elderly individuals, we defined
the minimum number of 5882 households to be randomly selected according to the expression
[d=(1500*10/3)/0.85], where d is the lowest number of
households being selected; 1500, the lowest number of
elderly individuals to enable the desired analyses; the
10/3 ration being 3 elderly for every 10 households; and
0.85, the expected rate of success for locating and interviewing in the selected households.20
For the random selection of households, we used a
two-staged cluster sampling, selected by a criterion of distribution proportional to size:
•• First stage – for sampling this stage, the permanent records of 72 census segments in the National Survey by
Household Sampling (PNAD) of 1995 were used, calculated as f1=(72*Di)/D, where f1 is the sampling fraction of this stage, Di is the number of households in
each segment; and D is the total number of households
in the city of São Paulo.
•• Second stage – to sample this stage, the number of
households to be randomly selected was calculated,
according to the number of census segments
(5882/72=81.69, approximate value used is 90), defined by f2=90/Di, based on the use of addresses, according to the PNAD of 1998.
The probability of a household belonging to the selected
sample was defined as f=f1*f2. In the selected households,
1852 eligible elderly were identified, of whom 1568 agreed
to participate in the study (84.67%).
The samples were supplemented with subjects aged
≥ 75 years and males including households located near
435
Campolina AG et al.
the selected areas or, at most, within the boundaries of
the districts of the selected areas.
To adjust the distribution of the sample to the composition of the population, weights were calculated for
each sex and age group. To compensate for unequal probabilities of random selection in the second stage due to
updating address lists for the 1998 PNAD, weights were
calculated for each census segment.
A detailed description of the methods employed in
the SABE survey can be found in the book O Projeto SABE
no Município de São Paulo: uma abordagem inicial [available
from http://www.fsp.usp.br/sabe].
In 2010, a new sample for the SABE survey was performed including 907 individuals of both genders, aged
≥ 60 years. The details of the methods employed are described in other publications.17, 18
Data collection
Data were collected through a questionnaire prepared by a
regional committee, composed of leading researchers from
each participating country and experts in specific research
topics. The instrument consists of eleven sections covering
aspects of daily life of the elderly: personal data, cognitive
assessment, health status, functional status, medications,
use of and access to services, network of family and social
support, employment history and income sources, housing
characteristics, anthropometry, flexibility and mobility.
The interviews were conducted at home, in the years
2000 and 2001 (the 2000 cohort) and in the years 2010,
2011 and 2012 (the 2010 cohort). Where there was difficulty or impossibility of the elderly to respond (due to
physical or cognitive problems), the participation of someone close was requested.17,21
Selected variables
Among the sociodemographic variables, the following
were considered: age, gender, living arrangements, marital status, ethnicity, education and income, based on relevant scientific literature.22, 23
Age was measured continuously, and categorized as
60-64 years, 65-69 years, 70-74 years, 75-79 years and 80
years and older. The family arrangement was classified as
living alone or not living alone. With regard to education,
information was collected and categorized as: no formal
education, primary school, high school, or undergraduate/graduate education. Marital status was categorized
into: single, married/common-law partner, widowed, or
divorced/separated. The employment status was classified as currently employed or unemployed.
Functional disability was defined as difficulty in performing one or more activities of daily living, including:
getting dressed, eating, bathing, toileting, walking around,
fecal and/or urinary incontinence, based on a validated
questionnaire already used in other publications.15,17, 24
Statistical Analysis and Ethical Aspects
Abridged life tables for the interval beginning with 60
years of age were calculated for the years 2000 and 2010
based on mortality and morbidity information10 and following steps described in demographics manuals,25 according to the Sullivan method.10
The information required for the application of the
Sullivan method is: specific mortality rates for a given population to allow the construction of a life table and the
prevalence of health states (disability) according to age.14
To calculate the disability-free life expectancy (DFLE),
the following applied:
The acronyms used were in accordance with the international notation, meaning:
lx = number of survivors at age x in the hypothetical
cohort of the table; YWD = number of years lived without
disability; DFLEx = sum of years lived without disability
for ages x and over, divided by lx.
The elderly population estimated for mid-year 2000
and mid-2010 was obtained from the censuses of 2000 and
2010, as well as information on deaths in the elderly population, gathered from Fundação Sistema Estadual de
Análise de Dados.26
In analyzes involving inference from the sample, the
information from each individual were weighted by the
inverse of the sampling fraction, with corrections for stratification and non-response.
The weights resulting from the sample design, i.e. the
inverse of the sampling fractions, were adjusted in order
to represent the population of the municipality by post-stratification. The weight of each individual indicates
how many inhabitants in the city it represents, and thus
the estimates of means and proportions are weighted to
represent population estimates.
Relative frequencies (%) were used to analyze the
prevalence and the Rao-Scott test for associations.
Analyses were performed using Microsoft Excel 2007
software (calculation of the life tables) and Stata, version 11.1 (descriptive analyzes of socio-demographic
variables and functional disability). In the latter case,
the weight of the sample (svy command) was taken into
account.
The research project was submitted to the respective
ethics committees of the countries involved. In Brazil, the
project was approved by the Ethics Committee on Human Research of the Faculty of Public Health, University
of São Paulo (COEP Notice 67/99 and COEP Notice 83/06
– Research Protocol no. 1345).
Data interpretation
Changes in expectations of healthy life were classified into
four possible situations:12
1. Absolute compression and relative compression of morbidity: there is a decrease in disabled life expectancy
(DLE) and an increase in percentage of disability-free
life expectancy (DFLE) in the overall life expectancy (LE).
2.Absolute compression and relative expansion of morbidity: there is a decrease in disabled life expectancy
(DLE) and a decrease in percentage of disability-free life
expectancy (DFLE) in the overall life expectancy (LE).
3. Absolute expansion and relative compression of morbidity: there is an increase in disabled life expectancy
(DLE) and an increase in percentage of disability-free
life expectancy (DFLE) in the overall life expectancy (LE).
4. Absolute expansion and relative expansion of morbidity: there is an increase in disabled life expectancy
(DLE) and a decrease in percentage of disability-free
life expectancy (DFLE) in the overall life expectancy
(LE).
Results
In 2000, we evaluated 2,143 elderly (response rate 84.6%),
58.6% being female. In 2010, 907 individuals (response
rate 91.6%) were assessed, 64.6% being female.
According to Table 1, in 2000, the percentage of women in the age group of 75 years or more was higher
than that of men. In 2010, however, the difference in
the distribution of the elderly by gender was not significant. Regarding ethnicity, there was a higher percentage of whites, both among men and women. In terms
of education, a higher percentage of men had graduated from high school and college, in 2000 and 2010. Widowhood was more prevalent among women than men,
also with a higher percentage of single women. We found
a higher percentage of men working at the time of the
study and women who lived alone, both in 2000 and
2010 (Table 1).
Table 1 Distribution of the elderly by sex according to socio-demographic variables. SABE1 Survey, São Paulo, Brazil, 2000 - 2010
Variable
Age range (years)
60-74
≥ 75 years
Total
Ethnicity
White
Mixed
Black
Yellow/other
Total
Education
No formal education
Primary school
High school
Undergraduate/graduate
Total
Marital status
Single
Married
Widowed
Divorced/separated
Total
Employment status
Currently employed
Currently unemployed
Total
Household arrangement
Living alone
Not living alone
Total
2000 (%) Female/Male
75.8 / 80.8
24.2 / 19.2
100.0
76.7 / 76.6
14.0 / 14.2
4.4 / 4.1
4.9 / 5.1
100.0
23.4 / 18.3
66.1 / 64.5
6.8 / 8.9
3.7 / 8.3
100.0
5.3 / 4.4
37.5 / 70.4
43.2 / 14.5
14.0 / 10.7
100.0
19.1 / 40.5
80.9 / 59.5
100.0
17.1 / 7.7
82.9 / 92.3
100.0
p
2010 (%) Female/Male
p
0.0030
56.5 / 63.0
43.5 / 37.0
100.0
0.0894
0.9535
62.8 / 62.2
25.7 / 22.7
6.4 / 8.8
5.1 / 6.2
100.0
0.4329
<0.000
17.3 / 12.6
70.9 / 66.5
6.9 / 11.5
5.0 / 9.4
100.0
0.0036
<0.000
4.9 / 3.5
35.4 / 76.8
51.4 / 15.6
8.2 / 4.1
100.0
<0.000
<0.000
12.7 / 39.9
87.3 / 60.1
100.0
<0.000
<0.000
21.4 / 8.3
78.6 / 91.7
100.0
<0.000
available from: http://www.fsp.usp.br/sabe.
1
437
Campolina AG et al.
Table 2 shows the prevalence of disability according to
age group. In general, there is a higher prevalence of disability with increasing age. The percentages of disability
were higher in 2010 (Table 2).
Table 3 presents, among elderly women and men, the
values for life expectancy (LE), disability-free life expectancy (DFLE), disabled life expectancy (DLE) and proportion of years to be lived free of disability (DFLE % in LE).
In both genders, we observe an increase in DFLE in
all age groups from 2000 to 2010. A decrease in DFLE %
is also observed in LE, both among females and males, in
all age groups (Table 3).
Discussion
The results showed that variations in disabled life expectancy and the proportion of years to be lived free of disability reveal a process of absolute and relative expansion
of morbidity (increase in DLE and decrease in DFLE percentage in overall LE) in progress among the elderly in
the city of São Paulo between 2000 and 2010.
Historically, increased LE is accompanied by improvements in the population’s health status. Today, however, this phenomenon no longer necessarily occurs in
terms of overall impact on the morbidity of a population,
because chronic diseases progressively replaced acute illnesses. Thus, the risk of illness is not only linked to the
risk of dying, but also the risk of becoming disabled.27 In
this context, the time trends of LE and DFLE, considered together, can help to answer questions relating to population dynamics in terms of morbidity compression,
expansion or balance.
Time series based on data from countries with low
mortality rates (Western Europe, Nordic Countries, North
America, Australia, Japan and New Zealand), covering a
Table 2 Prevalence of disability by sex and age group. SABE1 Survey, São Paulo, Brazil, 2000 - 2010
Age range
2000 (%)
(years)
Male
p
Female
60-64
15.79
36.83
23.65
40.7
65-69
18.01
30.97
36.38
49.48
70-74
22.13
37.44
38.26
43.47
75-79
32.63
48.66
38.33
59.51
≥ 80 years
43.62
54.72
47.86
68.46
Total
21.79
<0.0000
2010 (%)
39.02
p
0.5265
Male
p
38.9
0.0003
Female
54.33
p
0.0001
available from: http://www.fsp.usp.br/sabe.
1
Table 3 Life expectancy, disability-free life expectancy, disabled life expectancy and proportion (%) of years to be lived free
of disability, by gender and age group. SABE Survey, São Paulo, Brazil, 2000 - 2010
Gender and age group
LE1 (years)
DFLE2 (years)
DLE3 (years)
DFLE % in LE
2000 / 2010
2000 / 2010
2000 / 2010
2000 / 2010
Female
60-64
22.45 / 24.59
13. 01 / 11.37
9.44 / 13.22
57. 94 / 46.23
65-69
18.68 / 20.62
10.55 / 8.87
8.13 / 11.75
56.5 / 42.99
70-74
15.18 / 16.95
7.92 / 6.9
7.26 / 10.05
52.18 / 40.68
75-79
12.03 / 13.66
5.92 / 4.72
6.11 / 8.94
47.55 / 34.54
≥ 80 years
9.37 / 10.89
4.24 / 3.44
5.13 / 5.93
45.28 / 31.54
Male
1
60-64
17.65 / 19.73
13.3 / 12.56
4.35 / 7.17
75.34 / 63.65
65-69
14.56 / 16.36
10.5 / 9.75
4.06 / 6.61
72.1 / 59.58
70-74
11.86 / 13.34
8.01 / 7.73
3.85 / 5.61
67.53 / 57.96
75-79
9.45 / 10.71
5.79 / 6.00
3.66 / 4.71
61.31 / 56.01
≥ 80 years
7.5 / 8.6
4.23 / 4.48
3.27 / 4.12
56.38 / 52.14
life expectancy; 2 disability-free life expectancy; 3 disabled life expectancy.
period of 25 years, from 1970 to 1995, showed that the
increase in LE at 65 years is universal and constant. The
evolution of DFLE, in turn, seems to be stable, leading to
the possibility that the years gained in LE may occur at
the expense of disabled years.28
In the Global Burden of Disease Study, the analysis
of healthy life expectancy for 187 countries over the period 1990-2010 showed that as life expectancy increases,
the number of years of healthy life lost due to disability
has also increased in most countries, including Brazil.
This trend is consistent with the hypothesis of morbidity
expansion.29
In Europe, however, time series obtained from 14 countries in the period 1995-2004, show important differences
in the progression of a measure of healthy life expectancy
called “healthy life years.” Some countries show an increase in DFLE at 65 years or older (men: Austria, Belgium,
Italy, Finland, Germany; women: Belgium, Italy, Sweden),
while other countries show stagnation (men: France, Greece, Ireland, Spain; women: Austria, Denmark, UK, Finland,
France, Spain) or reduction (men: Denmark, Portugal, Netherlands, Sweden, United Kingdom; women: Germany,
Greece, Ireland, Netherlands, Portugal).28
In the United States of America (USA) for the last
years of the twentieth century, using data from the Medicare Current Beneficiary Surveys (MCBS) of 1992-1996,
Waidmann & Liu found a consistent decline in disability
rates for instrumental activities of daily living, at 65 years
of age or older.30
In face of these trend variations for DFLE in different
countries, two hypotheses have been raised. First, the decrease in mortality was accompanied by redistribution of
disability levels with, on the one hand, a reduction in the
prevalence of the most severe level and, on the other hand,
an increase in the prevalence of less severe levels. Thus,
years of life in good self-perceived health have generally
increased, while the trends in disabled life expectancy
have evolved differently depending on the level of disability severity: with decrease for the most serious and increase for milder cases.28
Secondly, the disability that could be attributed to
disease and aging would, in fact, be a consequence of limited education and training received by older generations. Among the variables that explain the variation in
DFLE in different contexts, education has been highlighted as one of the most important. Analyzes suggest that
future changes in education levels would continue to contribute to improving the functionality of the populations.31 A U.S. study showed by calculating DFLE between
1970 and 1990 that the compression of morbidity began
with individuals with more years of education.32 A study
from Austria about educational disparity trends showed
that, among women, there is a significant increase of the
difference in healthy life expectancy between people from
middle- and low-education backgrounds.33
Thus, the results presented in this study need to be
viewed with caution as the elderly population evaluated
presented a lower level of education compared with countries where DFLE time series are available, such as those
in Europe and North America. In populations with low
educational levels, a tendency to expansion of morbidity
would therefore be expected.
Moreover, we must also consider the fact that the disability measure used in the present study (basic activities of daily living) reflects a moderate to severe impairment of functionality. Unlike other countries where more
severe disabilities have not increased over the years, this
increase was found in the results presented. Since the
most severe disabilities are less affected by education as
a means of adaptation, these findings may suggest, in fact,
a process of morbidity expansion in the Brazilian elderly
population.
The self-reported information may also produce biases to the results. It is noteworthy, however, that studies
on healthy life expectancy have worked with self-reported diagnoses.34, 35 Research in Brazil shows the validity
of self-reported information to detect the health status.
Conditions such as cardiovascular disease and diabetes
seem to be properly reported by individuals, by virtue of
the universal coverage offered by the Brazilian health system.36
A study based on the National Survey by Household
Sampling (PNAD) from 1998 to 2003 also showed that
the use of another respondent does not modify the distribution of self-rated health among the elderly, or the
factors associated with it.37
Another aspect to be taken into account involves the
non-inclusion of elderly patients treated in institutions,
which could also lead to underestimation of the level of
disability, to the extent that this elderly population could
be experiencing higher prevalence of disability.
The fact that we worked with repeated cross-sectional
data, using prevalence rates in accordance with the Sullivan method, has disadvantages when trying to think in
terms of the changes that have been occurring in mortality and disability in the elderly population over time. Due
to its simplicity, however, the life tables in several studies
have been calculated based on the Sullivan method, which
has been the technique most widely used in many countries, thus facilitating future comparisons.38, 39
439
Campolina AG et al.
As research implications, it is considered that future
studies could use longitudinal designs enabling better
understanding of the transitions between health states,
especially the functional capacity.38 Studies including the
institutionalized population could bring more information about the evolution of disabled life expectancy among
the elderly. The use of the Disability-Adjusted Life Expectancy (DALE) indicator to compare the differences between
genders and sub-populations with different levels of disability severity might bring new information about the
differences in DFLE in the elderly population. Studies
that address the relationship between multimorbidity
and functional capacity may contribute to the understanding of the process of morbidity compression in this
population.
According to the results of this study, the expansion
of morbidity is an ongoing process in the elderly population in the municipality of São Paulo, for the period
2000-2010. Nevertheless, it has been shown that efforts
to promote health in populations of young adults (aged
65 or less) can lead to improvements in health and longevity in the elderly, without increasing health expenditures.27 In this sense, the health status seems to depend
on public efforts to combat smoking, obesity, low levels
of exercise, poor diet and excessive alcohol intake.40
Finally, we assume that a synergistic strategy to improve educational levels, improve nutritional status, improve working conditions and improve health behaviors
could preventively lead to improved functional capabilities and performance in essential activities of daily life,
contributing to the healthy life expectancy of future generations of elderly people.
Conclusion
Variations in disabled life expectancy and in the proportion of years to be lived free of disability showed that the
expansion of morbidity is an ongoing process in the elderly population in the municipality of São Paulo, from
2000 to 2010.
Resumo
A expansão da morbidade: tendências da expectativa de
vida saudável da população idosa
Objetivo: analisar as mudanças na expectativa de vida
(EV) e na expectativa de vida livre de incapacidade (EVLI)
dos indivíduos idosos do município de São Paulo, de 2000
a 2010, de modo a avaliar a ocorrência de compressão ou
expansão da morbidade nessa população.
Métodos: estudo transversal repetido, de base populacional, utilizando dados oficiais secundários para o município de São Paulo e dados obtidos a partir do Estudo
Saúde Bem-Estar e Envelhecimento (SABE). A incapacidade funcional foi definida como dificuldade para a realização de pelo menos uma atividade básica de vida diária. O método de Sullivan foi utilizado para o cálculo de
EV e EVLI para os anos de 2000 e 2010.
Resultados: de 2000 a 2010, observou-se um aumento
da expectativa de vida com incapacidade (EVCI) em todas as faixas etárias, em ambos os sexos. A proporção de
anos de vida livres de incapacidade, aos 60 anos, decresceu de 57,94% para 46,23% em mulheres, e de 75,34% para
63,65% em homens. Já aos 75 anos, esta proporção decresceu de 47,55% para 34,54% em mulheres, e de 61,31%
para 56,01% em homens.
Conclusão: a expansão da morbidade é um processo em
curso na população idosa do município de São Paulo, no
período de 2000 a 2010. Os resultados apresentados podem colaborar para a elaboração de estratégias preventivas e para o planejamento de serviços de saúde adequados às futuras gerações de idosos.
Palavras-chave: esperança de vida; expectativa de vida
ativa; tábuas de vida; morbidade; idoso.
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441
original article
Henriques ACPT et al.
Ana Ciléia Pinto Teixeira Henriques1*, Júlio César Garcia de Alencar2, Lívia Rocha de Miranda Pinto3, Rosa Maria Salani
Mota4, Raimunda Hermelinda Maia Macena5, Helvécio Neves Feitosa6, Francisco Herlânio Costa Carvalho7
Masters in Public Health, Federal University of Ceará and Lecturer at the metropolitan Faculty of Greater Fortaleza (Fametro), Fortaleza, CE, Brazil.
1
2
Medical Undergraduate Degree from the Federal University of Ceará, Fortaleza, CE, Brazil.
3
Medical Undergraduate Degree from the Federal University of Ceará, Fortaleza, CE, Brazil.
Doctorate in Collective Health, Federal University of Ceará, Fortaleza, CE, Brazil.
4
5
Adjunct Professor II of Physiotherapy, Federal University of Ceará, Fortaleza, CE Brazil.
6
Adjunct Professor at the Department of Maternal and Child Health, Medical School, Federal University of Ceará, Fortaleza, CE, Brazil.
Adjunct Professor at the Department of Maternal and Child Health and Adjunct Professor in the Masters program of Public Health, Department of Community Health, Federal University of Ceará, Fortaleza, CE, Brazil.
7
Summary
Study conducted at the Assis
Chateaubriand Maternity School, Fortaleza,
CE, Brazil
*Correspondence:
Address: Rua 521, nº 81, 2ª etapa
Conjunto Ceará
Fortaleza, CE – Brazil
Phone: +55 85 9944-9523
[email protected]
Objective: to analyze the changes in life expectancy (LE) and disability-free life
expectancy (DFLE) in São Paulo’s elderly population to assess the occurrence of
compression or expansion of morbidity, between 2000 and 2010.
Methods: cross-sectional and population survey, based on official data for the
city of São Paulo, Brazil, and data obtained from the Health, Well-Being and
Aging Survey (SABE). Functional disability was defined as difficulty in performing at least one basic activity of daily living. The Sullivan method was used to
calculate LE and DFLE for the years 2000 to 2010.
Results: from 2000 to 2010, there was an increase in disabled life expectancy
(DLE) in all age groups and both sexes. The proportion of years of life free of disability, at 60 years of age, decreased from 57.94% to 46.23% in women, and from
75.34% to 63.65% in men. At 75 years of age, this ratio decreased from 47.55% to
34.54% in women, and from 61.31% to 56.01% in men.
Conclusion: the expansion of morbidity is an ongoing process in the elderly population of the municipality of São Paulo, in the period 2000-2010. These results can contribute to the development of preventive strategies and planning
of adequate health services to future generations of seniors.
http://dx.doi.org/10.1590/1806-9282.60.05.012
Keywords: life expectancy, active life expectancy, life tables, morbidity, elderly.
Introduction
Cardiovascular diseases (CVD) are the leading cause of
death in women and men in Brazil, accounting for about
20% of deaths in individuals over 30 years.1 The difference in mortality between genders was noticed since the mid
1980s and, since then, occurrence has increased among
women.2
Certain conditions during pregnancy increase the
risk of hypertension, diabetes and atherosclerosis, resulting in a higher chance of coronary heart disease in women at a young age.2 Among the pathological conditions
that can compromise the normal course of pregnancy
and have close relationship with these changes, the pregnancy-induced hypertension syndromes (PHS) are the entities most clinically relevant, being the leading cause of
maternal and perinatal mortality in several studies in Brazil and worldwide.3,4
Recently, the relationship between the occurrence of
a pregnancy complicated by hypertension and the development of future complications was assessed, focusing
on cardiovascular disorders due to the magnitude and
importance they tend to assume in the context of public
health.5,6
The relationship between history of hypertension during pregnancy and the increased risk of CVD has been
described in many studies whose results indicate PHS as a
possible independent risk factor for cardiovascular disease, which deserves more attention when assessing the obstetric history of women, being even more important in the
presence of traditional non-modifiable risk factors.6-8
This study sought to identify if the history of PHS is
associated with changes in risk factors, morbidities and
the occurrence of cardiovascular events (CVE), in the long
run, characterizing the profile of cardiovascular risk (CVR)
calculated according to the Framingham Score (FRS).
Methods
This is a retrospective cohort study involving 60 women
who gave birth in the Assis Chateaubriand Maternity
School-UFC (MEAC) between 1992 and 2002 (mean follow-up of 15.2 years). MEAC, located in Fortaleza, state
of Ceará, is a tertiary hospital with specialized care in medium- and high-risk pregnancies, which treats patients
from the state capital and countryside.
The sample size was calculated assuming the prevalence of HBP at 27% and mean odds ratio at 19.3, according to a cohort study that assessed cardiovascular risk
factors in women with history of pregnancy-induced hypertension syndrome, for a power of 90% and significance level at 5%, resulting in a sample of 30 patients in each
group.9
The group of exposed subjects comprised 30 women
with any of the PHS classifications (three with chronic
hypertension simultaneous to index pregnancy, two with
pregnancy-induced hypertension, nine with mild preeclampsia, 13 with severe preeclampsia, two with preeclampsia superimposed on chronic hypertension, and
one with eclampsia), and the group of non-exposed individuals included 30 women without pathological obstetric history, randomly selected in the same perinatal period of the patients included in EG. One non-exposed
patient was selected for each exposed. For diagnosis and
classification of PHS, the patients’ medical records were
checked. The classification considered was that on the
day of hospital discharge and not on the day of admission.
At the time of selection, the participants who experienced any other obstetric complications during index
pregnancy, specifically multiple gestation, and those related to placental disorders, such as premature placental
detachment and placenta previa, were excluded, as well
as those with conditions knowingly related with future
cardiovascular risk, such as gestational diabetes. At the
time of the risk assessment, those who were pregnant or
in the postpartum period were excluded.
Patients selected in the first stage were invited for a
clinical assessment via an invitation letter, home visit and/
or telephone contact explaining all of the objectives of
the study, the exams to be conducted and emphasizing
their freedom to accept participation in the study or otherwise, without damages or loss. If they agreed, and after
signing the informed consent form, an assessment was
scheduled for evaluation of current clinical and obstetri-
cal variables, anthropometric assessment and laboratory
assessment. The assessment of cardiovascular risks was
conducted between March and September 2012.
The information collected in the medical records was
checked with the patient and other up to date information was sought. Risk information before and after the
index pregnancy was evaluated: age, race, parity, marital
status, occupation, education level, family income, current obstetric history, smoking habits, current illnesses,
practice of physical activity and family history of CVD
(confounding variables), and also occurrence of CVE, current morbidity and use of medication (dependent variables).
Other dependent variables were assessed in the physical exam: measuring of systolic blood pressure (SBP)
and diastolic blood pressure (DBP) with the use of the
semiautomatic monitor Microlife BP 3BTO-H, according
to the recommendations of the VI Brazilian Hypertension Guideline,10 weight and percentage of body fat assessments using a bioimpedance technique with the digital body analyzer scale Wiso W835, calculation of the
Body Mass Index (BMI) in accordance with the Brazilian
Obesity Guidelines 2009/2010,11 waist (WC), abdominal
(AC) and hip circumference (HC) measurements for calculation of the following anthropometric ratios: waist to
hip ratio (WHR), waist to height ratio (WHtR) and conicity index (C index), determined using the formula described by Valdez.12
Total cholesterol and fractions of HDL, LDL and
VLDL, triglycerides, AST and ALT, urea and creatinine
and fasting glucose were analyzed. Patients were advised
to fast for 12 hours and abstain from alcohol one day before collecting blood. The Tinder enzymatic method was
used to analyze the samples of total cholesterol and fractions and triglycerides, while the enzymatic method was
used for the fasting glucose analysis, the Jaffe method for
creatinine analysis and the UV kinetic method for evaluation of AST and ALT measurements.
The cardiovascular risk was also assessed using the
Framingham Risk Score, given its globally recognized validity, using the variables of age, LDL-C, HDL-C, blood
pressure, presence of diabetes and smoking habits. The
risk of cardiovascular events occurring in 10 years is estimated using the total points for each factor. The revised
Framingham Score for women was used.13
The data collected was tabulated and analyzed using
the Statistical Package for Social Sciences for Personal
Computer (SPSS-PC) software, version 18.0 with calculation of averages and standard deviations (SD) for analysis of the clinical and metabolic variables. The Kolmogo-
443
rov-Smirnov test was used to test the normality of the
variables, while the Student’s t-test was used to compare
the variables with the normal distribution, and the Mann-Whitney test for variables that were not normally distributed. Fisher’s exact test was used for qualitative variables. Statistical significance was considered when the
value of p < 0.05, with a confidence interval (CI) of 95%.
The odds ratio was calculated for the variables that were
statistically significant in the first analysis.
The project was approved by the Research Ethics Committee/MEAC under Report nº83/11.
Results
The groups did not differ in terms of age, parity, family
history of CVD, race, smoking habits, physical activity or
menopause.
Age at the time of delivery varied from 15 to 43 (average of 26.2 ± 7.7) years, and at the time of the risk assessment varied from 28 to 61 (average of 41.3 ± 8.8) years.
The patients did not differ in terms of prior obstetric
history at index pregnancy in relation to the number of
pregnancies (2.2 ± 2.3 x 3.0 ± 4.1; p = 0.78), parity (1.0 ±
1.9 x 1.2 ± 2.7, p = 0.26) and number of abortions (0.2 ±
0.4 x 0.8 ± 1.9; p = 0.25).
The number of years in school varied between zero
and eleven years (6.9 ± 3.1 x 6.8 ± 3.9; p = 0.91). Education level was not different between groups. Family income calculated using the number of minimum salaries
varied between 0.5 and 3 (1.5 ± 0.6 x 1.5 ± 0.7; p = 1.00).
Family income showed no difference between the groups,
either.
Table 1 presents the current clinical history of the patients collected via anamnesis during a clinical visit.
The diagnosis of at least one morbid condition was
informed by 40% of the women, showing a trend for a
greater number of women with a diagnosis in the group
of exposed patients.
High Blood Pressure (HBP) was the most frequent in
both groups, having been cited by 15 (25%) of patients in
association with other pathologies or otherwise. Type 2
diabetes mellitus (DM) was the second most reported disease, with eight cases (13.3%). Dyslipidemias also occupied a significant number of cited cases, accounting for
13.3% of cases.
Table 1 Current long-term medical history of women with (EG) and without pregnancy-induced hypertension (NEG).
MEAC-UFC. Fortaleza, 2012
Exposure
Non-exposed
Current diseases diagnosed/undergoing treatment
Exposed
n
%
n
%
p*
8
26.7
16
53.3
0.06*
-
Disease classification**
HBP
2
6.7
13
43.3
DM
1
3.3
7
23.3
Dyslipidemias
2
6.7
6
20
Occurrence of admissions
9
30
9
30
1.00*
Occurrence of CVE***
-
-
3
10
0.23**
Family history of CVD/CVE**
25
86.2
29
96.7
0.19**
HBP
22
75.8
21
70
-
Classification of the family history of CVD/CVE**
DM
7
24.1
14
46.6
AMI
4
13.8
7
23.3
Stroke
5
17.2
7
23.3
Antihypertensive
3
10
11
36.7
0.03**
Hypoglycemic
1
3.3
7
23.3
0.05**
Anticoagulant
1
3.3
2
6.7
1.00**
Fibrates/statins
1
3.3
4
13.3
0.35**
Hormonal contraceptives
1
3.3
4
13.3
0.35**
Use of medication
* Different statistical tests were used in the analysis: *X2 test; **Fisher’s test.
** The patients cited one or more pathologies.
*** HBP: high blood pressure; DM: diabetes mellitus; AMI: acute myocardial infarction; CHF: congestive heart failure; CVE: cardiovascular event; CVD: cardiovascular disease.
In relation to the occurrence of cardiovascular events,
three cases were documented among the 60 patients assessed (5%), all of which occurred in patients from the exposed group. In relation to the classification, the occurrence of one case of deep vein thrombosis was reported,
and two cases of cerebrovascular accidents. There was no
statistically significant difference between the groups in
relation to the occurrence of CVE.
After taking history of medication use by patients, we
found a statistically significant difference in the use of antihypertensive and hypoglycemic medication, with a trend
towards a difference between the groups. These medicines
are used to treat the illnesses cited most by the patients in
the study, with 23.3% of the sample reporting the use of an-
tihypertensive medication and 13.3%, the use of hypoglycemic medication. The OR was calculated for the use of antihypertensive medication, with a score of 5.2 (95CI: 1.3-21.2).
Table 2 presents the clinical and metabolic variables
related to an unfavorable cardiovascular profile, with averages and standard deviations for each group.
The weight of the patients analyzed varied between
45 and 99.9 kg with a mean of 70.4 ± 12.5 kg, and no statistically significant difference between the patients.
The BMI assessment showed a statistically significant
difference between the groups, with values between 19.7
and 46.9 kg/m2 and a mean of 29.9 ± 4.9. The highest BMI
values were found in the exposed group. The OR calculation was 1.13 (95CI: 1.00-1.3).
Table 2 Long-term clinical and metabolic characterization of women with (EG) and without pregnancy-induced
hypertension (NEG). MEAC-UFC. Fortaleza, 2012
Clinical and metabolic characteristics
Exposition
Non-exposed
Exposed
p*
Anthropometric variables
Weight (kg)
68.6±9.5
72.3±14.8
0.25*
Height (m)
1.54±0.1
1.52±0.1
0.06*
BMI (kg/m2)
28.5±3.2
31.2±5.9
0.03*
SBP (mmHg)
119.4±14.3
129.9±22.1
0.03*
DBP (mmHg)
78.9±11.3
83.5±15.0
0.19*
AC (cm)
93.1±9.8
97.2±12.4
0.16*
WC (cm)
86.5±8.6
89.1±11.8
0.32*
HC (cm)
102.7±8.3
106.9±11.1
0.10*
WHR
0.8±0.1
0.8±0.1
0.63*
C Index
1.2±0.1
1.2±0.1
0.84*
WHtR
0.6±0.1
0.6±0.1
0.12*
Biceps skin fold (mm)
13.1±5.3
15.6±8.7
0.19*
Body fat (%)
42.9±6.1
42.4±7.5
0.75*
Metabolic variables
Total cholesterol
177.6±40.1
191.6±30.8
0.13*
Triglycerides
143.4±97.5
155.1±73.3
0.60*
LDL-c cholesterol
104.7±31.4
124.0±28.4
0.02*
HDL-c cholesterol
42.2±11.1
39.9±10
0.40*
VLDL-c cholesterol
28.2±20.1
30.2±12.9
0.66*
AST
35.6±14.2
28.2±6.9
0.01*
ALT
30.2±15.2
23.8±7.9
0.06*
Urea
25.1±7.4
22.4±6.5
0.16*
Creatinine
0.7±0.1
0.8±0.3
0.17*
Fasting glucose
96.5±9.9
121.1±59.3
0.02**
*Different statistical tests were used in the analysis: *Student’ t-test; **Mann-Whitney.
BMI – Body Mass Index; SBP – systolic blood pressure; DBP – diastolic blood pressure; AC – abdominal circumference; WC – waist circumference; HC – hip circumference; WHR – waist to hip ratio; C Index – conicity index; WHtR – waist to height ratio; LDL-c - Low Density Lipid; HDL-c - High Density Lipoprotein; VLDL-c - Very Low Density Lipoprotein; AST - aspartate transaminase;
ALT - alanine aminotransferase.
445
SBP was also shown to be significantly different
between the groups, with values between 88 and 192
mmHg and a mean of 124.6±19.1 mmHg. The patients
in the exposed group presented higher average SBP values. The OR calculation was 1.03 (95CI: 1.00-1.06).
DBP varied between 56 and 111 mmHg, with a mean
of 81.2±13.3 mmHg, and no statistically significant difference between the groups.
The waist (WC), abdomen (AC) and hip circumference (HC) measurements were taken. The WC measurements
varied between 64 and 115 cm and presented a mean of
87.8±10.3 cm. The AC measurements varied between 69
and 119 cm, with a mean of 95.2±11.2 cm. The HC measurements varied between 82 and 133 cm, with a mean
of 104.7±9.9 cm. None of these presented a statistically
significant difference between groups.
The following anthropometric ratios were calculated:
waist to hip ratio (WHR), C Index and waist to height ratio (WHtR), with WHR values found varying between 0.70
and 0.97 with a mean of 0.8±0.1 in the sample. The C Index varied between 1.00 and 1.39, with a mean of 1.2±0.1.
The WHtR presented a greater variation between the
groups, varying between 0.42 and 0.79m with a mean of
0.6±0.1.There was no significant difference for the three
parameters analyzed above.
There were statistically significant differences for the
values of the LDL portion of the cholesterol and fasting
glucose, with higher values in the group of exposed patients. The LDL-c measurement varied between 50.2 and
189 mg/dL with a mean of 113.5±31.3. Fasting glucose
varied between 75 and 339 mg/dL with a mean of
108.8±43.9. An OR for LDL-c of 1.02 was found (95CI:
1.00-1.04) while for fasting glucose the OR was 1.03 (95CI:
1.00-1.07).
The total cholesterol values found in the sample varied between 115 and 276 mg/dL, with a mean of 184.5
± 36.1 mg/dL. The triglyceride values varied between 32
and 413 mg/dL with a mean of 149.3 ± 85.7 mg/dL while the HDL-c varied between 25 and 70 mg/dL with a
mean of 41.1 ± 10.6 mg/dL. There was no significant difference for the three parameters analyzed above.
The Framingham Risk Score was used for the cardiovascular risk assessment, estimating the risk of cardiovascular events in 10 years. Table 3 presents the scores relating to the Framingham Score calculation and the high
and low risk categorization based on this score.
The Framingham Score varied in relation to scores with
values between -7 and 22 with an average of 5.5 ± 6.6. The
OR for the Framingham Score was 1.09 (95CI: 1.00-1.19).
Three patients (5%) presented high cardiovascular
risk, all in the exposed group; however, this variable was
not statistically significant between the groups. When the
frequency of low risk classification for CVE, characterized as a risk of less than 10%, was analyzed a statistically
significant difference was found between the groups, with
all of the patients from the non-exposed group included
in this classification. Only two patients were classified as
having an intermediate risk (3.3%), characterized as a risk
between 10 and 20%.
Discussion
The groups of patients analyzed were similar in terms of
baseline characteristics in the period they started being
monitored in relation to age, number of pregnancies, parity, abortions and smoking habits, factors which could
cause a differentiated cardiovascular risk for age and smoking status are factors that affect the risk of CVE. Results
of current studies present a differentiated cardiovascular
profile for multiparous women and women with a history of consecutive abortions.14,15
In relation to current clinical history, the groups showed differentiated profiles for morbidity and use of medication, with the group of exposed patients holding a
more unfavorable morbidity profile when compared to
the non-exposed group.
Hypertension assumes a prominent role among the
group of morbidities stated, with a frequency higher than
expected for the general population found in this study.
Table 3 Long-term characterization of cardiovascular risk using the Framingham Score in women with (EG) and without
pregnancy-induced hypertension (NEG). MEAC-UFC. Fortaleza, 2012
Exposition
Non-exposed
p*
Exposed
Framingham score
3.7 ± 6.1
Low risk for CVE (n,%)
30
(100%)
7.5 ± 6.8
24
(80%)
0.03*
0.02**
High risk for CVE (n,%)
-
-
3
(10%)
0.11**
*Different statistical tests were used in the analysis: *Student’ t-test; **Fisher’s test. CVE – cardiovascular event; CVR – cardiovascular risk.
One study found a prevalence of 22.7% for HBP, a lower
value than that presented in our study.16
One study found that among 191 analyzed women
with a history of PHS, 32.5% were hypertensive 21 years
after the birth, a lower result than that found in this study,
which presented a frequency of 43.3% in the group of exposed patients.17
The study found different relative risks for occurrence of HBP in women with a history of PHS depending on
its seriousness. For women with a history of pregnancy-induced hypertension syndrome (PHS), the RR was found
to be 2.47 while for preeclampsia/eclampsia (PE/E) the
RR was 3.89.7
The frequency of DM and dyslipidemias in treatment
was also shown to be important in our study, with two
conditions reported by 13.3% of patients. In the group of
exposed patients, DM was reported by 23.3%, a high frequency considering that presented in a national study,
with a prevalence of 3.7% for diabetes mellitus.16
Analyzing the association between hypertensive disorders and the risk of maternal cardiovascular morbidity and type-2 diabetes after follow-up for an average of
14.6 years, one study found that women with pregnancy-induced hypertension presented a risk 3.12 times higher
for type 2 DM diagnosis, and in those with PE the risk
was 3.68 times higher.6
The use of medication was also statistically significant when comparing the history of women with PHS
and without exposure, but with a less striking risk gradient than that observed for the occurrence of hypertension. Women with a history of PHS presented RR of 1.89
and women with a history of PE/E had an RR of 1.90 for
the use of medication.7
The literature is vast in pointing out that women with
a history of PHS tend to present greater frequencies of
hypertension and DM diagnoses and the use of antihypertensive and hypoglycemic medications.6,7,18
The small number of cases of CVE did not enable a
significant different to be found between the groups, but
draws attention to the fact that all cases found occurred
in patients with a history of PHS.
Various studies evaluating CVE such as outcomes of
the follow-ups of women with a history of PHS indicate
a higher frequency of such events in this group.6,18,19
The practice of physical exercise was not shown to be
different between the groups, with a low frequency of
physical activity found in the sample studied. These results are comparable with the study which verified that
the majority of women interviewed (68%) did not practice physical activity.20
In relation to the clinical and metabolic assessment of
the patients, important differences were found, which are
significant to assessing the cardiovascular risk profile, the
main objective of the assessment. The BMI was found to
be significantly different in women with a history of PHS,
data which has already been presented in other studies.5,21
A study that analyzed 40 women with a history of
PHS and 14 with a history of normotensive pregnancies,
after a follow-up period of 14.6 years in the exposed group
and 15.9 years in the non-exposed group, found higher
BMI, AC and DBP values in women with a history of PHS,
with a mean BMI of 29.96 ± 6.13 kg/m2, AC of 93.15 ±
12.31 cm and DBP of 82 ± 11.86 mmHg in the exposed
group (p = 0.019, 0.026 and 0.047, respectively).5
In our study, the mean BMI measurements in the two
groups were higher than those found in this study5, demonstrating an even more unfavorable profile in this
sample in relation to excess weight/obesity, which was
found in 90% of the sample, drawing attention to the fact
that class 2 and 3 obesity were only found in patients with
a history of PHS. Another study found a prevalence of
47.7% for excess weight and obesity in women from São
Leopoldo, state of Rio Grande do Sul (Brazil).16
Studies indicate that excess weight and obesity represent a serious health risk and are strongly associated with
an increased risk of cardiovascular diseases, type 2 diabetes mellitus and metabolic disorders.22
One study that evaluated 168 pairs of women recruited between 1989 and 1997, 7.8 years after delivery, 105
of which had a history of PHS and 63 with a history of
PE, found higher average BP in patients with a history of
PHS, with mean SBP values equal to 115 mmHg, lower
than those presented by the patients in this study (129,
±22.1 mmHg).21
Fraser et al.23 found that approximately 20 years after pregnancy, women with a history of PHS or PE presented higher BMI, WC and BP when compared with women with a history of normotensive pregnancies. The
authors also found altered pressure values upon the birth
of SGA infants.
The AB and WC measurements, important parameters in the evaluation of central obesity24 had higher means
than the value considered appropriate according to national consensuses; however, this difference was not significant between groups.11,25
The accumulation of fat in women in the region of
the trunk and abdomen is related to changes occurring
in recent decades relating to dietary and lifestyle habits,
which could indicate an increasingly higher exposure to
cardiovascular risks.24
447
In addition to isolated anthropometric measurements,
three important anthropometric ratios were analyzed
(WHR, C Index and WHtR) already described in the literature in relation to their effectiveness in identifying the
differentiated cardiovascular risk profile.24,26,27
In this study, none of the ratios showed difference
between the groups evaluated, with only the C Index and
WHtR displaying higher values than recommended as
cut-off points for the assessment of cardiovascular risk
in women.26,27
Analyzing the blood chemistry characteristics, an unfavorable lipid profile was found in the exposed sample,
where the measurements of LDL cholesterol were higher,
which is concerning given that this portion of cholesterol is related with an unfavorable cardiovascular risk profile in the general population. The study found lower average LDL-c in the sample studied (120.7 ± 33.2), with no
statistically significant difference between the groups in
relation to this measurement.5
The measurements of the average total cholesterol,
triglycerides and VLDL were higher in the exposed group;
nevertheless, the differences were not found to be statistically significant, unlike the results of other studies showing a completely altered lipid profile in patients with a
history of PHS.21 The small sample may have been responsible for the lack of statistical significance in relation
to these values.
In both groups, the mean values for HDL-c portion
were lower than the value recommended by national consensuses as ideal parameters for the female population,
being the second most altered measurement in the sample studied (75.9%). The fraction of HDL cholesterol includes actions that contribute to protection of the vascular bed against atherogenesis, such as the removal of
oxidized lipids in LDL, inhibition of attachment of adhesion molecules and monocytes to the endothelium and
stimulation of nitric oxide release. Therefore the reduction in the levels of this portion of cholesterol, an abnormality demonstrated in other studies, is troublesome.28
The difference in fasting glucose was statistically significant, with exposed patients presenting the highest
averages. When analyzed for their adequacy in terms of
the parameters considered as normal for evaluation of
diabetes, all patients with values above that recommended by the Brazilian Diabetes Society,11 i.e., 126 mg/dL,
were allocated to the exposed group.
Regarding the cardiovascular risk profile calculated
using FRS, the study showed that 16% of women with a
history of PHS had Framingham risk scores 30% higher
than women with a history of normotensive pregnancies,
even after adjustment for pre-pregnancy BMI. The authors believe that the explanation for the entire cohort
being assessed as a low risk profile for CVE resides in the
young age of the patients in the study, having found an
average risk of 3%, with evidence of variations related to
complications during pregnancy.23
In this study, we only found five patients in the sample (8.5%) with an unfavorable cardiovascular risk profile according to the Framingham Score. Even in small
numbers, the occurrence of an unfavorable risk profile
for CVE (intermediate or high) in the exposed group indicates the need for research with larger samples in these groups, temporally assessing the modification of this
risk according to exposure.
The body of evidence published so far demonstrates
the need for a differentiated clinical attention for patients
with a history of PHS, encouraging more specific and earlier reviews in this group of patients, with postpartum
and long-term follow-up focusing on the prevention of
cardiovascular events.
Despite the clear association with an increased risk
in patients with a history of PHS, due to the similarity
between the groups regarding other risk factors for CVD,
the findings should be interpreted with caution. The number of patients can be considered small. It was difficult
to find many of the patients owing to changes of address
and phone numbers, and a considerable number refused
to participate. Although random, there may have been a
selection of cases very similar to the controls, which may
also have contributed to the identification of few differences for the risk assessments.
The analysis was able to provide a relatively long follow up, which should be considered very positive. However, follow up times with longer monitoring periods are
needed, especially after the implementation of protective measures to investigate whether the risk can be modified or be considered as unchanging, similar to a family
history of CVD. That is, there is still doubt as to whether
PHS is an event associated with increased risk of CVE alone or if this increased risk is only associated with other
factors that it causes: increased central obesity, metabolic syndrome, hyperglycemia, and hypertension.
Further investigations should be made into the relationship between the severity of PHS and its recurrence with the
severity of interference in cardiovascular risk, and the association with other sexual and reproductive factors, inclu-
ding isolated and joint adverse perinatal outcomes. The ideal
would be to assess the real value of each obstetric factor (e.g.
prematurity, low birth weight and fetal growth restriction)
on the risk of the development of future CVE.
Conclusion
The study showed an unfavorable cardiovascular risk profile in patients with a history of PHS, demonstrated
through changes in anthropometric measurements such
as BMI and WC, as well as metabolic measurements, such
as the lipid profile (LDL-c cholesterol), and glycemic measurements (fasting glucose), even in patients considered
young for the prevalence of such conditions. The patients
in the exposed group presented higher Framingham Risk
Scores.
Resumo
Síndrome hipertensiva gestacional e risco cardiovascular.
Objetivo: caracterizar o perfil de risco cardiovascular em
longo prazo de mulheres com história de síndrome hipertensiva da gestação (SHG) e compará-lo ao de mulheres
com histórico de gestação normotensa.
Métodos: este é um estudo de coorte retrospectivo que incluiu 60 mulheres que deram à luz na MEAC-UFC entre
os anos de 1992 e 2002 (seguimento médio de 15,2 anos).
O grupo de exposição (GE) foi composto por 30 mulheres
em qualquer categoria de SHG, e o grupo de não exposição (GNE) compreendeu 30 mulheres sem história de patologia obstétrica. Foram avaliados os dados antropométricos e laboratoriais associados ao risco cardiovascular e
calculados o escore Framingham (variáveis dependentes).
Para variáveis quantitativas, foram usados o teste t de Student e o teste de Mann-Whitney. Para variáveis qualitativas, aplicou-se o teste exato de Fisher. Considerou-se a significância estatística como p<0,05.
Resultados: GE apresentou valores mais altos de IMC (p=0,03,
OR=1,13, IC 1,00-1,3), PAS (p=0,03, OR=1,03, IC 1,00-1,06),
LDL-C (p=0,02, OR=1,02, IC 1,00-1,04) e glicose de jejum
(p=0,02, OR=1,03, IC 1,00-1,07), além de valores mais altos
no escore de Framingham (p=0,03, OR=1,09, IC 1,00-1,19).
As mulheres em GE usaram medicamentos anti-hipertensivos com mais frequência (p=0,03, OR=5,2, IC 1,3-21,2).
Conclusão: foi encontrado um perfil de risco cardiovascular desfavorável nas pacientes com história de SHG em
comparação com as mulheres sem esse histórico.
Palavras-chave: pré-eclâmpsia; hipertensão induzida pela
gravidez; doenças cardiovasculares; fatores de risco; epidemiologia.
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original article
Suely Pires Curti1*, Cristina Adelaide Figueiredo1, Maria Isabel de Oliveira1, Joelma Queiroz Andrade2, Marcelo Zugaib2,
Denise Araújo Lapa Pedreira3, Edison Luiz Durigon4
Adolfo Lutz Institute – Center of Respiratory Diseases, São Paulo, SP, Brazil.
1
2
Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo, SP, Brazil.
3
Department of Pathology, Faculty of Medicine, University of São Paulo, SP, Brazil.
Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
4
Summary
*Correspondence:
Instituto Adolfo Lutz
Address: Av. Dr. Arnaldo, 355
Phone: +55 11 3068-2906
Fax: +55 11 3088-3753
[email protected]
http://dx.doi.org/10.1590/1806-9282.60.05.013
Objective: rubella during the early stages of pregnancy can lead to severe birth
defects known as congenital rubella syndrome (CRS). Samples collected from
pregnant women with symptoms and suspected of congenital rubella infection
between 1996 and 2008 were analyzed.
Methods: a total of 23 amniotic fluid samples, 16 fetal blood samples, 1 product of conception and 1 placenta were analyzed by serology and RT-PCR.
Results: all patients presented positive serology for IgG / IgM antibodies to rubella virus. Among neonates, 16 were IgG-positive, 9 were IgM-positive and 4
were negative for both antibodies. Of the 25 samples analyzed in this study, 24
were positive by RT-PCR. Changes in ultrasound were found in 15 (60%) of 25
fetuses infected with rubella virus. Fetal death and miscarriage were reported in
10 (40%) of the 25 cases analyzed. The rubella virus was amplified by PCR in all
fetuses with abnormal ultrasound compatible with rubella. Fetal death and abortion were reported in 10 of 25 cases analyzed.
Conclusion: this study, based on primary maternal rubella infection definitely
confirms the good sensitivity and specificity of RT-PCR using amniotic fluid and
ultrasound. The results showed that molecular assays are important tools in the
early diagnosis of rubella and congenital rubella syndrome.
Keywords: ultrasonography, prenatal, rubella syndrome, congenital, amniotic
fluid, diagnosis, RT-PCR, serology.
Introduction
Rubella virus (RV) usually causes a mild exanthematous
disease frequently accompanied by adenopathy and occasional arthralgia. However, infection during pregnancy,
particularly during the first trimester, can lead to severe
birth defects known as congenital rubella syndrome (CRS).1
Congenital rubella infection causes fetal death and a spectrum of birth defects known as congenital rubella syndrome. The syndrome affects multiple organ systems and
common abnormalities include deafness, congenital heart
disease, cataracts and mental retardation.2 Traditionally,
detection of fetal viral infection relies on isolation and culture of virus or maternal and cord blood seroconversion.3
Viral culture and subsequent identification from mother
and fetuses and/or amniotic fluid has been the gold standard. This method is slow, taking between 1 to 3 weeks to
obtain a positive result. Maternal serology may also lack
sensitivity and can be difficult to interpret. Advances in diagnostic techniques such as the polymerase chain reaction
(PCR) allows rapid detection and it is a highly sensitive
method. Recently, the diagnosis of congenital rubella infection is based mainly on the detection of rubella virus in
amniotic fluid (AF) by RT-PCR4,5 or detection of rubella virus specific IgM antibody in fetal blood.6,7
Rapid and accurate identification of the causative virus is increasingly important and can guide prenatal management as well as identify the need for long-term followup. In addition, in many countries, clinically recognized
maternal rubella during the first 8 weeks of gestation is
an indication for therapeutic abortion due to the high
incidence of congenital defects. This is why there are only
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Curti SP et al.
a few PD studies in which rubella RNA is available. Infection prior to conception does not present a risk to the fetus, but when primary rubella infection occurs in the first
12 weeks of pregnancy, rubella virus will cross the placenta and induce generalized and persistent fetal infection
in about 80% of cases.3,8 Spontaneous abortion may take
place in up to 20% of cases when rubella occurs in the first
8 weeks of pregnancy.9,10 During the past 10 years, nationwide epidemics of rubella occurred approximately every
5 years in São Paulo, Brazil, namely in 1995, 2000 and
2007.1,11 To reduce rubella transmission and prevent CRS,
a nationwide campaign to vaccinate women and men
against rubella was initiated in Brazil in 2001 and 2008.
The World Health Organization (WHO) has estimated
that more than 100,000 cases of CRS occur in developing countries every year; this represents a considerable
social and economic burden. This study presents a series
of CRI cases based on an integrated analysis of clinical
features, serological and molecular investigation. Furthermore, all cases were submitted to clinical and laboratory analyses and a complete follow-up involving neonatal care in pediatric units by otorhinolaryngologists,
ophthalmologists and cardiologists was carried out, thus
providing a unique opportunity for the study of intrauterine transmission of rubella and its consequences to
the fetus and newborn.
Methods
Patients
Forty patients with abnormal ultrasound findings, clinical signs and serological evidence of rubella, were studied prospectively between 1996 and 2008 at the Fetal Medicine Unit, University of São Paulo. No termination of
pregnancy was performed since Brazilian law does not allow it. Maternal age from 16 to 39 years (mean: 25 years).
Gestational age at the time of acute rubella was based on
the last menstrual period (LPM) and the first trimester
ultrasound scan using the crown-rump length measurement. The diagnostic strategy was based on seroconversion and/or the detection of rubella virus-specific IgM.
Newborn follow-up was based on the presence of structural malformations, rubella antibodies at birth and at 3
months of age, echocardiographic alterations, brainstem
evoked response audiometry, and ophthalmic pathology.
Among the pregnant women, 20 had symptoms, 15 had
fever, exanthema and lymphadenopathy; 2 had fever and
exanthema, and 3 had exanthema and lymphadenopathy.
This study was previously submitted to and approved by
the Ethics Committee on Research with Human Beings
at University of São Paulo (623/CEP).
Samples
The first maternal serum had been collected in the Clinical Hospital of the University’s School of Medicine and
the second sample after 15 days of the first collection.
Newborn samples were obtained from umbilical cord
blood at 3 months of age. Amniocentesis was offered to
all 40 patients with clinical signs of rubella before 12
weeks of gestation, but only in 23 cases, amniocentesis
was performed. The samples were obtained at 21 weeks
of gestation and 6 weeks after the onset of clinical signs
of rubella. A total of 23 amniotic fluid samples, 16 fetal
blood samples, 1 product of conception and 1 placenta
were analyzed (Table 1). All samples were stored at -80°C
until use.
Serological assays
Detection of IgG and IgM specific antibodies to rubella
virus was performed using a commercial enzyme immunoassay (Siemens, Marbuy, Germany) according to the
manufacturer’s instructions.
RNA extraction and reverse transcription
Viral RNA was extracted either directly from clinical specimens or from viral culture. Samples (200 µL) and inoculated cell cultures (300 µL) were extracted using Tri reagent (Molecular Research Center, Inc., Cincinnati, OH,
USA) according to the manufacturer’s protocol. Placental tissue was processed using the viral RNA Mini Kit (Invitrogen™ Life Technologies, Carlsbad, CA, USA). RV RNA
was detected by RT-PCR as described previously.4 The expected lengths of RT-PCR products synthesized using R2
and R7 (nt 8807–8991) and R11 and R8c (nt 8826–8968)
primer pairs were 185 and 146 bp, respectively. All reactions were performed using positive and negative controls.
Results
Maternal and newborn serology
All pregnant women studied had positive serology results
for IgG and IgM to rubella virus in the first or second sample (Table 1). In 5 of the subjects, a second sample could
not be collected (np). Of the 16 newborns that had serum
samples, 11 (68,75%) were IgM-positive and 5 (31,2%) were
IgM-negative. Serology could not be performed in 9 of the
newborn due to fetal death or miscarriage.
RT-PCR
Of the 25 samples analyzed in this study, 24 were positive by RT-PCR. The amniotic fluid samples negative on
RT-PCR were confirmed by virus isolation. As a control,
Table 1 Serological and PCR analysis in 25 pregnant women and newborn and outcome
Pregnant
Newborn
Serology
Case/year
Gestational
of week
symptom
IgM
RV detection
IgG
Serology
IgM
1o sample
2o sample
1o sample
2o sample
Sample
RT-PCT
Outcome
IgG
01/1996
11.2
pos
pos
neg
pos
AF
pos
pos
pos
Live
02/1996
11.9
pos
pos
neg
pos
AF
pos
pos
pos
Live
03/1996
10.9
pos
pos
neg
pos
AF
pos
pos
pos
Live
04/1996
11
pos
pos
neg
pos
AF
pos
pos
pos
Live
05/1998
11.5
pos
pos
pos
pos
AF
pos
pos
pos
Live
06/1999
11.4
pos
pos
pos
pos
AF
pos
pos
pos
Live
07/1999
12.0
pos
pos
neg
pos
AF
pos
np
np
Miscarriage
08/2000
4.4
pos
np
pos
np
AF
pos
np
np
Fetal death
09/2000
7.5
neg
pos
neg
pos
AF
pos
pos
pos
Live
10/2000
4.1
pos
neg
pos
pos
AF
pos
np
np
Fetal death
11/2000
11.2
neg
pos
neg
pos
AF
pos
pos
pos
Live
12/2000
1.4
pos
np
pos
np
AF
pos
np
np
Fetal death
13/2000
11.4
pos
pos
pos
pos
AF
pos
pos
pos
Live
14/2000
2
pos
pos
pos
pos
AF
pos
np
np
Fetal death
15/2000
5
pos
np
pos
np
AF
pos
np
np
Fetal death
16/2000
11.4
neg
pos
neg
pos
AF
pos
neg
pos
Live
17/2000
11.7
pos
pos
neg
pos
AF
pos
pos
pos
Live
18/2000
8.2
pos
pos
pos
pos
AF
pos
neg
pos
Live
19/2000
10.8
pos
neg
pos
pos
AF
pos
neg
pos
Live
20/2000
10.3
pos
pos
neg
pos
AF
pos
neg
neg
Miscarriage
21/2001
7.4
pos
neg
pos
pos
AF
pos
np
np
Fetal death
22/2001
11.5
pos
neg
pos
pos
AF
pos
pos
neg
Live
23/2001
4.5
pos
pos
pos
pos
AF
neg
neg
pos
Live
24/2002
4
pos
pos
np
np
POC
pos
np
np
Fetal death
25/2008
12
pos
pos
pos
np
Placenta
pos
np
np
Fetal death
pos: positive; neg: negative; POC: product of conception; AF: amniotic fluid; np: no processed
the 25 samples in this study were submitted to PCR for
other viruses such as parvovirus B19, herpes virus simplex 1 and 2, and cytomegalovirus. Twenty-four samples
were negative for these viruses, only one (case 23) was positive for cytomegalovirus.
Evaluation of ultrasound
Alterations were found in several follow-up evaluations
by ultrasound in 15 (60%) of the 25 fetuses infected with
rubella virus. Miscarriage and fetal death were reported
in 10 (40%) of the 25 cases analyzed (Table 2). Rubella virus was amplified by PCR in all fetuses showing ultra
sound alterations compatible with rubella: growth restriction, hepatomegaly, hydrocephaly, ventricular septal defect, intracranial calcifications, oligohydramnios, with
more than one abnormality in some cases (Table 2). Although rare in congenital rubella, in one case (case 7) the
cranial cap was absent, with cerebral tissue floating in
amniotic fluid.
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Curti SP et al.
Table 2 Results of the analysis of the ultrasound and newborn of the 25 cases analyzed
Case
Ultrasonographic examination
Newborn follow-up
1
Without alterations
Live/cataract
2
Decrease AF, growth restriction
Live
3
Hydrocephaly
Live/speech impairments
4
Insufficient tricuspide
Live
5
Decrease AF, hepatomegaly
Live
6
Without alterations
Live
7
Cranial cap absent
Miscarriage
8
Growth restriction
Fetal death
9
Without alterations
Live/bilateral deep deafness
10
Hydrocephaly, growth restriction, ventricular septal defect
Fetal death
11
Without alterations
Live/ventricular septal defect
12
Growth restriction
Fetal death
13
Atrial septal defect, aortic stenosis
Live/arthritis 6 months
14
Fetal death
Fetal death
15
Hepatomegaly, hydrocephaly, intracranial calcifications
Fetal death
16
Without alterations
Live
17
Without alterations
Live
18
Oligohydramnios, arterial canal patency, aortic stenosis
Live
19
Without alterations
Live
20
Without alterations
Miscarriage
21
Ventricular septal defect
Fetal death
22
Without alterations
Live
23
Without alterations
Live
24
Growth restriction
Fetal death
25
Hydrocephaly, growth restriction, ventricular septal defect
Fetal death
In case no 25, fetus showed ultrasound abnormalities:
echogenic fetal bowel, growth retardation, oligohydramnios, placentomegaly, pericardial effusion, cardiomegaly,
hepatomegaly, and ascites. Fetal death occurred at the
29th week of gestation. Rubella virus was amplified from
placenta and histological diagnosis of the placenta showed active chronic villitis and chorioamnionitis, villous
fibrosis, focal calcifications, and thrombotic vasculopathy with avascular villi and hemorrhagic endovasculitis.
Newborn follow-up
In the total group of live newborn, 10 newborns did not
show change in the ultrasound during the prenatal, but
after birth, one newborn showed bilateral deep deafness
and other ventricular septal defects. There were 6 cases
in which virological analyses of the amniotic fluid samples were positive while the newborn showed no signs of
congenital rubella syndrome (cases 6, 16, 17, 19, 22 and
23). These results indicate that not all infected babies developed the congenital disorder. Out of 15 live newborn
with alterations in ultrasound, 4 lived without sequela,
and 3 presented alterations after birth: speech impairments and arthritis (Table 2).
Discussion
Historically, rubella and congenital rubella syndrome
have been an important public health challenge in Brazil. Despite the fact that rubella vaccination was initiated in 1992, regular outbreaks of the disease have been reported since the beginning of 1995 and have continued
until 2007.12,13 Between 1999 and 2008, a large number
of rubella cases were reported throughout the country,
with the highest incidence among adults and a steady increase in the number of CRI and CRS cases.11,14 The impact of CRS in life and in the economy of the country was
high; therefore, it became necessary to accelerate control
and, ultimately, eliminate rubella virus transmission. CRI
cases may play an important role as virus-shedders and
in the continuation of rubella transmission within the
community. Therefore, identifying them to prevent fur-
ther rubella transmission is also important in the context of rubella elimination.15
The clinical diagnosis of acute rubella infection in
pregnancy is extremely difficult. The rash is not very specific or particularly apparent, and most infectious cases
are subclinical.2,3 Therefore, demonstration of seroconversion and presence of high IgM titers is the primary
mode of diagnosis of acute rubella in pregnancy. Unfortunately, booking serum samples are often not available.
The risk of congenital infection may usually be estimated by establishing the gestational age at the time of maternal infection. However, diagnosis of intrauterine infection is difficult because often maternal serology is
inconclusive especially when infection occurs between
the 13th and 20th weeks of gestation.2 Direct methods of
diagnosing fetal infection by PCR are therefore essential
for early diagnosis as shown by another report.1 Our results showed that all pregnant women studied had positive serology results for IgG and IgM to rubella virus in
the first or second sample. In the present cases, prenatal
diagnosis was performed after 21 weeks of gestation and
the time elapsed between the onset of maternal infection
and the procedure was longer than 6 weeks, reducing
false-negative results.
The humoral immune response of infants with CRS differs from that of naturally infected or immunized children.2
Laboratory confirmation is based on the detection of rubella specific IgM and IgG antibodies and low avidity antibody.
Fetal blood is not taken for this purpose until about 22 weeks
of gestation, when fetal IgM becomes detectable; however,
virus-specific IgM levels may be low at this time and therefore false-negative results may be obtained. Rubella is slower than in postnatal infection and low avidity can be detected for a longer period.2,3,16 The present study confirms the
above findings by means of IgM negative in the sera of the
four newborns infected. However, these newborns that had
no detectable IgM were positive for RV RNA by PCR assays.
Among these cases, one newborn showed alterations by ultrasound, arterial canal patency and aortic stenosis another miscarriage. It has also been reported that false-positive
IgM results can be obtained with sera from patients with
other acute viral infection, such as measles, parvovirus B19,
cytomegalovirus and Epstein-Barr virus infection.17 Our
finding that one newborn with rubella IgM reactivity was
diagnosed with cytomegalovirus infection supports this observation. It becomes evident that unspecific stimulation of
immune cells or cross-reacting antibodies can also be found
in the fetal system.
Concerning the PCR results, rubella was detected in
all amniotic fluid samples of mothers of infected fetuses.
Macé et al.5 report involving 45 pregnant mothers of rubella-infected fetuses, (83%) were rubella-positive. Furthermore, results similar to these were reported by Bosma et al.4 and Jin et al.18 PCR is a rapid and sensitive
molecular method and it has not been applied systematically to CRS cases. It can be used in conjunction with serology for the diagnosis of acute infection and also for
the diagnosis of pre and post-natal CRS since the serological results can be inconclusive.3,4,5,19 However, detection of rubella viral RNA in AF which may be obtained
from amniocentesis at about 12 weeks of gestation allows
confirmation of fetal infection. The time between maternal infection and fetal sampling is an important consideration in prenatal diagnosis. The optimal sampling interval between maternal infection and fetal sampling
should be 6 to 8 weeks for amniotic fluid and fetal blood.5
The consequences of rubella during pregnancy may be
the birth of a child with congenital anomalies, which may
be severe, and multiple birth of a child apparently normal
or spontaneous abortion.20 Rubella virus generally establishes a chronic nonlytic infection in the fetus and has the
potential to infect any organs.21,22 The rubella virus teratogenic process most probably begins when placental infection occurs during maternal viremia, leading to dissemination of the virus throughout the fetus. In addition, tissues
from different organs of fetuses with CRS revealed teratogenic effects, such as reduced cell size and number compared with control, which was suggestive of mitotic inhibition or perhaps due to rubella induced chromosomal
breaks.21 Even when the fetus is infected, it survives in most
cases; the pregnancy continues and premature births or
stillbirths can occur.3 In our results, the most common ultrasonographic prenatal rubella infection findings were
heart and amniotic fluid anomalies. Hydrocephaly, although rare in congenital rubella, was observed in tree cases. Absence of the skullcap with cerebral tissue floating in
the amniotic fluid was diagnosed in case no 7 and the virus was detected in the placenta, liver, and central nervous
system. Miller et al.9 also report two fetuses with the same
alterations. A ventricular septal defect was observed in two
cases and an atrial septal defect associated with aortic stenosis was diagnosed in one case. Case no 25 also showed
several changes in placenta due to viral replication. As a result of prenatal diagnosis, it is clear that not all infected
fetuses developed CRS. The simplest hypothesis implies
that the decisive parameter is the replication level of the
virus in the fetus, i.e. when virus replication in the fetus
surpasses a certain critical level, the fetus would then develop CRS. If this does not occur, the fetus would remain
undisturbed. It is noteworthy that rubella genome was de-
455
Curti SP et al.
tected in the amniotic fluid, POC and placenta due to the
infection of the mothers and also from a newborn that
died with severe congenital disorders. In addition, antibodies IgG against rubella virus were transmitted from the
mother to the fetus, while IgM antibodies were not transmitted but produced in the fetus from around 20 weeks
of gestation. However, these antibodies could not eliminate the virus from the fetal body although they had neutralizing activity. Elimination of the virus from the infected tissue is dependent on cell-mediated immunity. At
around 1 year of age, its ability becomes completely mature and thus the body is able to eliminate the virus. In
contrast, in the case of infected eye lens, the virus cannot
be completely eliminated from the lens. Once the virus enters the lens, it replicates and persists without elimination.3
In Brazil there are not many reports about CRI, because the diagnosis of infection with rubella virus during pregnancy or congenital rubella syndrome is performed only after the birth of the child. In some countries,
the risk of disease in the first trimester justifies termination of pregnancy without prenatal diagnosis, which is
not allowed in Brazil, because Brazilian law does not allow therapeutic abortion.
Resumo
Diagnóstico pré-natal de infecção congênita por rubéola, em São Paulo, Brasil.
Objetivo: a rubéola, durante os primeiros estágios da gravidez, pode levar a graves defeitos congênitos, conhecidos como síndrome da rubéola congênita (SRC). Amostras de gestantes com sintomas e suspeitas da rubéola
congênita foram coletadas entre 1996 e 2008.
Métodos: um total de 23 amostras de fluido amniótico,
16 amostras de sangue fetal, um produto da concepção e
uma placenta foram analisados por sorologia e PCR.
Resultados: todas as gestantes apresentaram sorologia
positiva para IgG/IgM para o vírus da rubéola. Entre os
recém-nascidos, 14 apresentaram anticorpos IgG positivos e 11 foram os anticorpos IgM positivos. Das 25 amostras analisadas neste estudo, 24 eram positivas por RT-PCR. Alterações na ultrassonografia foram encontradas
em 15 (60%) dos 25 fetos infectados com o vírus da rubéola. Morte fetal e aborto espontâneo foram reportados
em 10 (40%) dos 25 casos analisados. O vírus da rubéola
foi amplificado por PCR em todos os fetos que apresentaram alterações na ultrassonografia, compatíveis com a
rubéola. Morte fetal e aborto foram relatados em 10 dos
25 casos analisados.
Conclusão: os resultados mostraram que os ensaios moleculares são ferramentas importantes para o diagnóstico
precoce da rubéola e da síndrome da rubéola congênita.
Palavras-chave: ultrassonografia pré-natal; síndrome da
rubéola congênita; líquido amniótico; diagnóstico, RT-PCR; sorologia.
References
1. Andrade JQ, Bunduki V, Curti SP, Figueiredo CA, de Oliveira MI, Zugaib M.
Rubella in pregnancy: intrauterine transmission and perinatal outcome
during a Brazilian epidemic. J Clin Virol. 2006;35:285-91.
2. Hobman T, Chantler J. Rubella virus. In: Knipe DM, Howley PM, editors.
Fields virology. Philadelphia: Lippincott Williams & Wilkins; 2007. v.1,
p.1069-100.
3. Best JM. Rubella. Semin Fetal Neonatal Med. 2007;12:182-92.
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JE. Use of PCR for prenatal and postnatal diagnosis of congenital rubella.
J Clin Microbiol. 1995;33:2881-7.
5. Macé M, D Cointe, C Six, Levy-Bruhl, Parent du Châtelet I, Ingrand D, et al.
Diagnostic value of reverse transcription-PCR of amniotic fluid for prenatal
diagnosis of congenital rubella infection in pregnant women with confirmed
primary rubella infection. J Clin Microbiol. 2004;42:4818-20.
6. Daffos F, Forestier F, Grangeot-Keros L, Lebon P, Chartier M, Pillot J. Prenatal
diagnosis of congenital rubella. Lancet. 1984;2:1-3.
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detection of rubella-specific IgM in fetal sera. Prenat Diagn. 1985;5:21-6.
8. Enders G, Jonatha W. Prenatal diagnosis of intrauterine rubella. Infection.
1987;15:162-4.
9. Miller E, Cradock-Watson JE, Pollock TM. Consequences of confirmed
maternal rubella at successive stages of pregnancy. Lancet. 1982;2:781-4.
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analysis of rubella vírus strains during an outbreak in São Paulo, 2007-2008.
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www.cve.saude.sp.gov.br/htm/Cve_dex.htm.
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departamento de vigilância epidemiológica, Surtos de rubéola no Brasil,
atualização. Available from: http://portal.saude.gov.br/portal/saude/.
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et al. Epidemiological and molecular characterization of rubella virus isolated
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16. Thomas HI, Morgan-Capner P, Cradock-Watson JE, Enders G, Best JM,
O’Shea S. Slow maturation of IgG1 avidity and persistence of specific IgM
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original article
Dietary patterns are associated with general and central obesity in elderly living in a Brazilian city
Dietary patterns are associated with general and central obesity in
elderly living in a Brazilian city
Priscila Lucelia Moreira1, Jose Eduardo Corrente2, Paulo Jose Fortes Villas Boas3, Ana Lucia Anjos Ferreira4*
Dietitian, MSc, Department of Internal Medicine, Botucatu Medical School at Sao Paulo State University (UNESP), Botucatu, SP, Brazil.
1
2
Mathematician, Associate Professor, Department of Biostatistics, Botucatu, Institute of Biosciences at Sao Paulo State University (UNESP), Botucatu, SP, Brazil.
3
Professor, Department of Internal Medicine, Botucatu Medical School at Sao Paulo State University (UNESP), Botucatu, SP, Brazil.
Associate Professor, Department of Internal Medicine at Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, SP, Brazil.
4
Summary
Study conducted at the Department of
Internal Medicine. Botucatu Medical
School, Sao Paulo State University
(UNESP), Botucatu, SP, Brazil
*Correspondence:
Department of Internal Medicine at
Botucatu Medical School,
Sao Paulo State University (UNESP)
Botucatu, SP – Brazil
Phone/Fax: +55 14 3880-1171
3882-2238
[email protected]
Objective: dietary pattern evaluation is often used in order to determine wheter a diet is healthy, as well as to predict the onset of diseases. This study aimed
to identify dietary patterns, and to examine their associations with general (body
mass index) and central (waist circumference and waist-to-hip ratio) obesity in
community-living elderly in a Brazilian city.
Methods: this cross-sectional study included 126 elderly subjects aged 60 or older (57.1% females and mean age 74.2 ± 6.46 years). Anthropometric variables,
weight, height, waist (WC) and hip (HC) circumferences, were measured. Body
mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Answers to a
Food Frequency Questionnaire were interpreted by Principal Component Analysis in order to identify dietary patterns.
Results: five dietary patterns were identified and named as prudent (fruit, vegetables and meat), sweets and fats (pastries, sugary foods, fatty foods, whole milk),
typical Brazilian (fried eggs, cooked beans, beef, candy, string beans, fried cassava), Mediterranean (fruit, vegetables, olive oil and nuts) and traditional meal
(rice and beans). Moderate and high adherences to the Mediterranean pattern
were protective factors to general and central obesity (WHR). High adherence to
prudent was also protective to central obesity (WC).
Conclusion: adherences to the dietary patterns prudent and Mediterranean
were protective factors to general and central obesity in elderly.
http://dx.doi.org/10.1590/1806-9282.60.05.014
Keywords: elderly, dietary pattern, obesity, anthropometry, cross-sectional studies.
Introduction
The elderly population in Brazil has increased rapidly,1
and by 2025, will rank sixth largest in the world.2 The
number of elders, in relation to the total Brazilian population, grew from 7.3% in 1991, to 8.56% in 20003 and
to 10.8% in 2010.4 Mortality and birth rate reductions
correspond to factors associated with the elderly population rising.5 The World Health Organization considers ages 60+ or 65+ years when referring to the older
population in developing and developed countries, respectively.
Diet is a changeable factor that can help healthy aging. The analysis of nutrient intake does not result in a
clear understanding of its quality. Since a daily diet conRev Assoc Med Bras 2014; 60(5):457-464
sists of a diversity of foods and a large concentration of
nutrients, the analysis of dietary patterns becomes the
best alternative to evaluating healthy behaviors.6,7
Diet and nutrition have been studied as factors for
promoting and maintaining health throughout life.8 Dietary patterns have been associated with non-communicable chronic diseases,9-13 mortality,14-16 cognitive function,17 obesity10,12,18-19 and the protective effect on being
overweight.14,18,20-21
Unhealthy dietary patterns (sugar, fat, processed foods
and refined grains) can be found in overweight younger
adults20,22 as well as in the elderly.10,19 Moreover, such patterns can be related to measurements above the recom-
457
Moreira PL et al.
mended waist circumference and waist-to-hip ratio in
adults and the elderly.12,23 Several studies have shown that
healthy food (fruit, vegetable, low fat meat and fiber rich
products) may promote a protective effect against general [body mass index, (BMI)]18,20, 24 and central [waist-tohip ratio (WHR) and waist circumference (WC)] obesity.14,18,21, 24
Although it seems obvious that unhealthy dietary patterns may be associated with obesity, this issue may be debatable. In fact, other studies have identified no positive
relationship between obesity and unhealthy dietary patterns in both elderly14 and younger adults.25 Examining
children and adults, previous study showed the association between healthy food intake (fruit and vegetables) and
obesity reduction (adiposity/overweight) is not clear.26
Thus, the current study attempts to characterize the dietary patterns, and verify their association with health-related variables in the elderly population of a Brazilian city.
Methods
Subjects
The study was conducted in Botucatu, which is a city with
130,201 inhabitants27 and is located (22º53’09” south latitude, 48°26’42” west longitude) in the state of Sao Paulo, Brazil. Data were collected at the participants’ houses from May to November 2008. The sample consisted of
126 individuals older than ≥ 60 years. Inclusion criteria
were pre-defined as follows: residing in a community (city
of Botucatu, SP, Brazil),3 60 years and agreeing to participate in the study. The sample (base sample) was sourced
from a database obtained in a previous study conducted
in Botucatu City.28 From the base sample of 365 elderly,
185 subjects were randomly selected to be part of a database of the current study. The initial contact was made
by telephone, followed by a household interview, anthropometric measurements and a dietary record. Fifty-nine
subjects were excluded due to several reasons (refusal to
participate in the study, 34; unanswered phone, 13; death,
3; use of vitamins, 3; absence of records of their primary
health, 3; hospitalization, 2; absence, 1), with 126 subjects remaining. All procedures were in accordance with
the Helsinki Declaration for human rights, and the study
was approved by the Research Ethics Committee of the
Botucatu School of Medicine (UNESP). All patients or
their legal guardians signed a Free-Consent form.
Anthropometric measures
Weight and height were measured according to Lohman
(1988).29 Subjects were weighted dressed in light clothing
and barefoot in a digital scale (Toledo®), with 150 kg ca-
pacity and 0.1 kg accuracy. Height was recorded using a
portable stadiometer (Sanny®) with the subjects standing erect without shoes and with the feet together. For
bedridden elderly persons, the weight and height were estimated by the Chumlea formula.30-31
Body mass index (BMI) was calculated by dividing
the weight by height squared (kilograms/meters2) of the
subjects. The classification of nutrition status by BMI
was performed according to cutoff points established by
the Pan American Health Organization32 [low weight (≤
23 kg/m2), normal weight for height (23 < BMI < 28 kg/
m2) and overweight (≥ 28 kg/m2 overweight and obese ≥
30 kg/m2)].
Waist (WC) and hip (HC) circumferences were measured using a non-elastic tape. WC was measured with
the subject standing up, at the end of normal expiration,
by using the tape at a point midway between the inferior margin of the lowest rib and the iliac crest, whereas
HC was recorded at maximum posterior extension of the
hip29. The waist-to-hip ratio (WHR) was calculated by dividing WC by HC. Waist circumference was considered
high when its values were above 88 cm for women and
102 cm for men.33 WHR was considered elevated when its
values were above 0.85 for women and 1 for men.33 All
measurements were performed by the same investigator
(1st author of this study), with the same tape, stadiometer and scale.
Dietary intakes
The evaluation of the estimated daily intake was performed by using a food frequency questionnaire (FFQ)34
with adaptation (inclusion of cooked sweet potatoes, chicory, pepper, lime, mango, beets, green beans, poached
eggs and nuts). Besides daily intake, the FFQ was used to
evaluate the individuals’ frequency of consumption (from
0-10 times a day, week, month or year).35
Statistical analysis
The dietary intake information obtained by FFQ was analyzed and interpreted for identification of the dietary
patterns by exploratory factor analysis (Principal Component Analysis, PCA). In this method, data are summarized, and correlated variables are grouped.
Some food items were excluded from the analysis because they displayed low intake frequency. One hundred
and twenty-one food items were included in the PCA.
Kaiser-Mayer-Olkin (KMO) measurement and Barlett’s Test of Spherecity (BTS) were applied to evaluate
PCA applicability. In order to obtain the dietary patterns,
varimax rotation was used, and based on the correlation
matrix. The number of factors was determined by taking
into account loading values greater than or equal to 0.3,
and the percentage of explained variation. Food items
with negative loadings were excluded from each pattern.
Cronbach’s α coefficient was obtained for each factor by evaluating the consistency and the characteristics
of each food and the effect of its exclusion on the final
coefficient value.
The scores of individual intake were obtained from
the dietary patterns and categorized into tertiles, i.e. the
1st as low, the 2nd as moderate and 3rd as high adherence
to the pattern.
The variables BMI [(presence (BMI ≥ 28 kg/m2) or absence (BMI ≤ 28 kg/m2) of overweight)] and WC [presence (≥ 88cm, women; ≥ 102cm, men) or absence (<88cm,
women; <102cm, men) of increased values] were categorized dichotomously. For the waist-hip ratio, the elevated values were considered when they

were above 0.85 for
women and 1 for men.
Logistic regression models were fitted by considering
general or central obesity as an outcome and the variables
of interest (low, moderate and high adherence to dietary
patterns) as an explanatory control for age and sex.
All analyses were performed by software SAS (Statistical Analysis System, Cary, North Caroline) and SPSS
(Statistical Package for Social Sciences, Armonk, New
York) for Windows, versions 9.2 and 19.0, respectively.
Results
One hundred and twenty-six elderly individuals were evaluated. Of these, 72 (57.1%) were females aged 65 to 95
years (74.2 ± 6.46). By using the Kaiser-Mayer-Olkin (KMO)
coefficient and the Barlett Test of Sphericity (BTS), appropriate conditions were verified for application of Principal Component Analysis (PCA) and patterns (factors)
were extracted. By factor analysis, it was possible to identify 5 dietary patterns in this population, which explained
21.11% of the total variance of food intake. In our study,
the pattern labeled as prudent presented the highest variance percentage (5.64%), followed by sweets and fats
(4.48%), typical Brazilian pattern (4.05%), Mediterranean
(3.72%) and traditional meal (3.22%).
Table 1 shows the anthropometrics characteristics of
126 elderly. Table 2 shows the factor loading (obtained
after varimax rotation) of each food item composing the
dietary factor (pattern) found. The items with factor loading higher than 0.3 were maintained in order to compose
the dietary pattern. Cronbach’s α coefficient was analyzed
for each factor (pattern). Variability of food intake by in-
dividual in that pattern was considered high when the
Cronbach’s α coefficient value was higher than 0.6. On
the other hand, variability was considered low when that
coefficient values was lower than 0.6.
Table 1 Anthropometric characteristics of participants
All
Men
Women
Number of subjects2
126
54
72
Age (y)1
74.1 (6.6)
73.4 (6.3)
74.7 (6.8)
27.2 (4.7)
26.3 (4.2)
28 (5)
20 (15.9)
8 (14.8)
12 (16.7)
29 (23)
9 (16.7)
20 (27.8)
WC (cm)1
94 (12.4)
97.4 (11.4)
91.5 (12.6)
HC (cm)
104.8 (10.6) 101.1 (6.7)
107.6 (11.9)
0.9 (0.09)
0.85 (0.06)
BMI (kg/m )
2
1
Overweight
(BMI 28 – 30 kg/m2)2
Obese
(BMI ≥ 30 kg/m2)2
1
WHR1
0.96 (0.08)
BMI, body mass index; WC, waist circumference; HC, hip circumference; WHR, waist to hip ratio.
1
data are mean (± standard deviation).
2
data are number (%).
Table 2 Foods and factor loading for the five dietary
patterns identified
Foods
Pattern Pattern Pattern Pattern Pattern
1
2
3
4
5
Cooked rice
- 0.206
0.142
0.287
- 0.029
0.367
Sweet biscuits
0.134
0.385
0.082
- 0.135
0.113
French fries
- 0.055
0.323
0.223
- 0.180 - 0.066
Boiled potato
0.424
- 0.113
0.116
0.060
Boiled cassava
0.488
- 0.166
0.193
- 0.443 - 0.098
Fried cassava
0.148
0.127
0.329
- 0.245 - 0.067
Baked sweet potatoes - 0.010
0.400
0.040
- 0.011
0.135
0.163
Sugar
- 0.180
0.420
0.214
- 0.278
0.165
Ice cream
0.051
0.337
0.126
0.175
0.025
Cooked beans
- 0.350
0.025
0.384
0.028
0.330
Chard
0.372
- 0.217
0.201
0.448
0.204
Watercress
0.423
0.161
- 0.031
0.049
0.035
Chicory
0.458
- 0.106
0.137
- 0.338
0.057
Escarole
0.425
- 0.274
0.104
- 0.262
0.174
Broccoli
0.706
- 0.299
0.247
0.152
0.025
Cauliflower
0.506
- 0.036
0.216
0.356
0.085
Spinach
0.415
0.218
- 0.225 - 0.020
0.142
Courgette
0.663
- 0.199
0.074
0.108
Eggplant
0.695
- 0.228 - 0.030 - 0.121 - 0.081
Chayote
0.556
- 0.184
0.274
- 0.201 - 0.074
- 0.303
Pepper
0.230
0.002
0.296
0.335
0.105
Tomatoes
0.315
0.171
0.136
0.328
0.030
String beans
0.609
- 0.233
0.335
- 0.050
0.109
(continue)
459
Moreira PL et al.
Table 2 Foods and factor loading for the five dietary
patterns identified (continuation)
Foods
Pattern Pattern Pattern Pattern Pattern
1
2
3
4
5
used in the preparation of Brazilian people’s meals, and
was called the typical Brazilian pattern. Pattern 4 was rich
in fruits, vegetables, monounsaturated fats (olive oil, avocado and nuts), low amounts of foods from animal sources, and was designated the Mediterranean. Pattern 5 contained cooked rice and beans, which represented the basis
of Brazilian meals, and was labeled the traditional meal.
Beets
0.491
- 0.320
0.284
0.139
- 0.178
Carrots
0.545
- 0.039
0.107
0.124
0.047
Pineapple
0.517
- 0.098
0.098
- 0.329 - 0.045
Avocado
0.197
- 0.002
0.042
0.366
0.124
Banana
0.050
0.064
0.241
0.374
- 0.133
Table 3 Food items of the five factors identified
Guava
0.308
0.314
- 0.288
0.050
- 0.006
Dietary pattern
Foods
Orange
0.307
0.036
0.165
0.252
0.020
Dietary pattern 1
Broccoli, eggplant, courgette,
Lime
0.102
0.313
0.120
0.242
0.250
Prudent
string beans, chayote, carrots,
Apple
0.319
0.020
0.125
- 0.094 - 0.033
Papaya
0.437
- 0.044
0.140
0.134
Mango
0.378
0.040
- 0.046 - 0.271 - 0.507
strawberry, chicory, papaya,
Watermelon
0.537
- 0.088
0.102
- 0.394 - 0.122
escarole, boiled potato,
Strawberry
0.466
- 0.038
0.181
- 0.199 - 0.174
watercress, fish, spinach, mango,
chard, peach, apple, orange,
Variance explained: 5.64%
0.030
watermelon, pineapple,
cauliflower, beets, boiled cassava,
Peach
0.353
0.234
- 0.106
0.107
Whole milk
- 0.035
0.355
0.168
- 0.098
- 0.423
0.147
Prato cheese
0.086
0.151
0.093
0.328
- 0.375
Dietary pattern 2
Homemade sweets, pizza, sweets
Parmesan cheese
0.300
0.153
- 0.280
0.375
- 0.009
Sweets and fats
in syrup, salt cake, sugar, sweet
Mozzarella cheese
0.106
0.235
0.125
0.388
- 0.289
milk, baked sweet potatoes, sweet
Milk cream
0.240
0.317
- 0.092 - 0.031 - 0.166
biscuits, pork, whole milk, ice
cream, industrialized sweets,
Olive oil
0.287
0.064
0.014
0.443
Fried eggs
- 0.141
0.189
0.422
- 0.090 - 0.045
Boiled eggs
0.051
0.303
0.150
- 0.035
0.103
Poached eggs
0.228
0.362
- 0.177 - 0.106
0.067
Fish
0.421
0.036
- 0.283
0.268
0.171
- 0.032
Salt cake
0.215
0.442
- 0.206 - 0.196
0.005
Pizza
0.147
0.533
0.126
0.153
- 0.112
Beef
0.152
- 0.187
0.359
0.020
0.096
Pork
- 0.066
0.367
0.173
- 0.244 - 0.087
Poultry
0.306
- 0.159 - 0.082 - 0.201
0.209
Homemade sweets
0.143
0.537
- 0.120
0.071
- 0.024
Industrialized sweets - 0.072
0.325
0.293
- 0.236
0.120
Sweet milk
- 0.034
0.416
0.182
0.017
0.036
Candy
- 0.093
0.298
0.358
- 0.046
0.151
Sweets in syrup
0.248
0.490
- 0.145 - 0.122 - 0.132
Nuts
0.153
- 0.108 - 0.190
0.320
0.003
Cronbach’s α
0.768
0.518
0.57
0.821
0.348
poultry
Table 3 shows the five patterns identified. Dietary pattern
1 was mainly loaded with fruit, vegetables and low fat meat
and was labeled as prudent. Pattern 2 was mainly rich in
foods with high energy, such as, sweets, pork, and french
fries and was named the sweets and fats. Pattern 3 contained legumes, meat, vegetables, fried eggs and fried carbohydrates (cassava, in this case), which are foods usually
french fries, milk cream, guava,
lime, poached eggs, boiled eggs
Dietary pattern 3
Fried eggs, cooked beans, beef,
Typical Brazilian pattern
candy, string beans, fried cassava
Variance Explained: 4.05%
Dietary pattern 4
Chard, olive oil, mozzarella
Mediterranean
cheese, parmesan cheese, banana,
avocado, cauliflower, pepper,
Dietary pattern 5
Cooked rice, cooked beans
tomatoes, prato cheese, nuts
Traditional meal
Associations between dietary pattern adherence versus general and central obesity are showed in Table 4. The adherence to Mediterranean and prudent patterns were protective
factors for obesity. In detail, moderated adherence to Mediterranean was a protective factor to general obesity (values
above the recommended BMI) (OR 0.243, 95% CI 0.0930.635). High adherence to the same pattern was a protective
factor to central obesity (values above the recommended for
WHR) (OR 0.027, 95% CI 0.109-0.706). High adherence to
prudent was a protective factor for central obesity (values
above the recommended WC) (OR 0.160, 95% CI 0.031-0.835).
Table 4 Dietary patterns and overweight (BMI), WHR and WC association in 126 elderly
Variables
Adherence to
BMI
WHR
WC
patterns
Pattern 1
High
Prudent
Moderate
Low
p-value
OR (95% CI)
p-value
OR (95% CI)
p-value
OR (95% CI)
0.22
0.626 (0.250-1.567)
0.36
1.015 (0.402-2.561)
0.01
0.160 (0.031-0.835)
0.47
1.051 (0.433-2.554)
0.03
1.390 (0.455-4.241)
–
1.0
0.05
–
2.158 (0.870-5.356)
1.0
–
1.0
Pattern 2
High
0.77
0.679 (0.265-1.735)
0.28
0.595 (0.227-1.557)
0.09
0.249 (0.061-1.025)
Sweets and fats
Moderate
0.39
0.585 (0.233-1.473)
0.76
0.869 (0.348-2.172)
0.75
0.596 (0.190-1.872)
Low
–
1.0
–
1.0
–
1.0
Pattern 3
High
0.57
0.497 (0.202-1.226)
0.77
1.026 (0.414-2.544)
0.20
1.451 (0.429-4.907)
Typical Brazilian
Moderate
0.15
0.386 (0.151-0.991)
0.51
1.318 (0.522-3.328)
0.18
0.558 (0.145-2.153)
Pattern 4
High
0.33
0.332 (0.133-0.830)
0.02
0.027 (0.109-0.706)
0.29
0.357 (0.104-1.222)
Mediterranean
Moderate
0.04
0.243 (0.093-0.635)
0.94
0.513 (0.207-1.269)
0.48
0.402 (0.114-1.419)
Low
Low
–
–
1.0
–
1.0
–
1.0
1.0
–
–
1.0
1.0
Pattern 5
High
0.94
0.860 (0.346-2.139)
0.10
0.586 (0.229-1.494)
0.98
0.995 (0.297-3.341)
Traditional meal
Moderate
0.68
0.785 (0.313-1.969)
0.18
1.316 (0.530-3.269)
0.98
1.009 (0.300-3.391)
Low
–
1.0
–
1.0
–
1.0
BMI, body mass index; WHR, waist to hip ratio; WC, waist circumference.
Odds ratio adjusted for age and sex.
Discussion
The current study conducted in community-living elderly identified five dietary patterns named as prudent, sweets
and fats, typical Brazilian pattern, Mediterranean and
traditional meal. Our results showed that moderate and
high adherences to the Mediterranean pattern are protective factors to general (BMI) and central obesity (WHR),
respectively; whereas high adherence to prudent may have
a beneficial effect on central obesity (WC). To our knowledge, this is the first time that dietary patterns and their
effects on general and central obesity in Brazilian elderly have been evaluated.
The 5 patterns found represented 21.11% of the total variance. This value was similar (21%) to that found
in a previous study conducted on Italians elderly, which
identified 4 dietary patterns.10 The FFQ currently applied34 has been used in previous studies.36-38 The good
reproducibility for associations currently observed by applying FFQ and PCA was also identified by another author.39 In fact, FFQ can be applied in epidemiological
studies, since it is able to associate the frequency of intake of certain dietary factors with variables of interest.34,40
The named Mediterranean pattern included health
foods from a plant source, olive oil, avocados and nuts,
although also comprised some kind of cheeses with high
fat amount (mozzarella, parmesan and prato cheese).
Since it contains foods that are rich in monounsaturat-
ed fatty acids, it is considered to be a cardioprotective
diet.16,41-42 The inverse association between adherence to
the Mediterranean diet and cardiovascular disease has
been shown in a study that examined event occurrences
(myocardial infarction, stroke, or death from cardiovascular causes) in the 4.8 years of follow-up in a population
aged 55-80 years,43 and by meta-analysis that evaluated
mortality risk.44 This diet pattern also has been associated with lower general mortality in Europe.16,45-46
Our results showed that moderate and high adherences to Mediterranean pattern are protective factors to general (BMI) and central obesity (WHR), respectively. Previous study identified the Mediterranean pattern and WHR
as factors independently associated with the ischemic stroke
occurrence in elderly and other adults.47 Spanish researchers found an inverse association between obesity (BMI and
WC) and a healthy life style, including adherence to the
Mediterranean diet48 by the elderly. Examining adults, prospective studies also have shown that adherence to the
Mediterranean diet was negatively associated with WC49
and with weight gain (≥ 5 kg).50 On the other hand, some
studies found no protective effect of the Mediterranean
diet on weight gain in adults and elderly.51-53
Also found in other studies,8,14,21 the prudent dietary
pattern has been associated with the reduction of all-cause
mortality54 and hypertension.12,55 In the current study,
461
Moreira PL et al.
high adherence to this dietary pattern was a protective
factor for central obesity (WC). Similar results were identified in the elderly56-58 and adults.56,59-60
The sweets and fats pattern has been found in several
researches.8,16,61 It represents a concerning dietary pattern
since it contains foods that are associated with the high
prevalence of chronic diseases.8 In fact, elderly people tend
to show a high percentage of non-communicable chronic
diseases, such as hypertension, cardiovascular diseases and
diabetes.62-64 However, it is important to note that other
factors are associated with chronic diseases, such as genetic ones. Absence of the association between obesity and
this dietary pattern was currently found. Conversely, the
dietary pattern containing sweets and fats was associated
with a high BMI in the elderly and adults,59,61,65 elevated
WC in adults59,61 and high mortality in elderly men.16
Another dietary pattern, typical Brazilian, represents
the standard Brazilian meal which contains a type of meat,
a legume (beans, in this case), a fried carbohydrate (cassava), a vegetable, and fried eggs. Examining results from
the Family Budget Study (children, adults and elderly individuals), a study found that the typical Brazilian pattern contains foods that were noteworthy in the dietary
representation from all Brazilian regions.66 The absence
of the association with this dietary pattern and obesity
was evident in our study. To the best of our knowledge,
no studies have addressed this issue. Therefore, comparisons cannot be made.
The traditional meal pattern is incorporated into the
population’s habits from the North to the South of Brazil and in all age ranges.66 The comparison of this pattern
with international studies is not actually feasible since
this combination of rice and beans is typically Brazilian.
We did not identify the association of this dietary pattern
with obesity in the elderly. Some national studies performed in adult populations showed that this pattern
was inversely associated with WC61 and was associated
with lower risk factors for weight gain.61,67-68
It is important to emphasize that the metabolic syndrome is a frequent condition among elderly69-71 and that
central obesity is a risk factor for this disorder.72 In the
present study, we showed central obesity may have been
protected by high adherence to the Mediterranean and
prudent patterns, and general obesity may have been protected by moderated adherence to the Mediterranean dietary pattern. Recent systematic review identified evidences of adherence to the Mediterranean diet and protective
effects in adults and elderly subjects with metabolic syndrome.73 Thus, the adherence to those dietary patterns
may contribute to diminishing the metabolic syndrome
prevalence.
It is worth mentioning that the current population
cannot be considered representative of the whole Brazilian community-living elderly, since they came from a Brazilian small city. Other limiting factors should also be
mentioned, such as the sample size, study design (crosssectional) and method for identifying the dietary patterns,
which is not defined as a gold standard.
Although longitudinal studies with larger numbers
of elderly are needed, health programs, including the formulation of policies for dietary education and health care,
should be adopted to prevent obesity in older people.
Conclusion
In summary, our study identified that moderate and high
adherences to the Mediterranean pattern are protective
factors to general (BMI) and central obesity (WHR), whereas high adherence to the prudent pattern is a protective factor to central obesity (WC) in the elderly.
In spite of the limitations discussed, the outcomes
of this study contribute to the literature by furthering
the knowledge of the relationship between dietary patterns and obesity in the elderly. Longitudinal studies using a larger sample size are needed to test the hypothesis
of the possible obesity protecting effect of the Mediterranean and prudent dietary patterns on community-living elders.
Author’s contributions
PLM performed the data collection. JEC and PLM worked on data analysis and interpretation, and statistical
analysis. PJFVB, PLM, JEC and ALAF wrote the final version of the manuscript. All authors evaluated the results,
contributed with their comments, and approved the final version of the manuscript before submission for publication.
Acknowledgements
We thank São Paulo’s State Research Support Foundation (FAPESP # 2007/57545-8; # 2007/07455-2), which
supported this study in part, and the Research Support
Group at Botucatu School of Medicine at Sao Paulo State University (UNESP), which helped in the statistical
analysis. We appreciate Barbara B. Golner’s editing of the
English grammar.
Supported by
FAPESP (#2007/57545-8, Master’s Scholarship; #2007/074552, Research Financial Support).
Resumo
Padrões alimentares associados com obesidade geral e
central em idosos residentes em uma cidade brasileira.
Objetivo: a avaliação do padrão alimentar é muitas vezes usada para determinar se uma dieta é saudável, bem
como para predizer o aparecimento de doenças. Este estudo teve como objetivo identificar padrões alimentares
e analisar as suas associações com obesidade geral (índice de massa corporal) e central (circunferência da cintura e relação cintura-quadril) em idosos residentes em comunidade em uma cidade brasileira.
Métodos: este estudo transversal incluiu 126 idosos com
60 anos ou mais de idade (57,1% do sexo feminino e média de idade 74,2 ± 6,46 anos). As variáveis antropométri
cas [peso, altura, circunferências da cintura (CC) e do quadril (CQ)] foram mensuradas. Foram calculados o índice
de massa corporal (IMC) e relação cintura-quadril (RCQ).
As respostas a um questionário de frequência alimentar
foram interpretadas por Análise de Componentes Principais, a fim de identificar os padrões alimentares.
Resultados: cinco padrões alimentares foram identificados e nomeados como prudente (frutas, legumes e carne), doces e gorduras (alimentos de pastelaria, doces, alimentos gordurosos, leite integral), padrão tipicamente
brasileiro (ovos fritos, feijão cozido, carne, caramelo, vagens, mandioca frita), Mediterrâneo (frutas, legumes, azeite de oliva e nozes) e tradicional (arroz e feijão). Adesões
moderada e alta ao padrão Mediterrâneo foram fatores
de proteção para obesidade geral e central (RCQ). Alta
adesão ao padrão prudente também foi protetor contra
a obesidade central (CC).
Conclusão: adesões aos padrões alimentares prudente e
Mediterrâneo foram fatores de proteção para obesidade
geral e central em idosos.
Palavras-chave: idoso, padrão alimentar, obesidade, antropometria, estudos transversais.
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original article
Giordana Campos Braga1*, Suelem Taís Pereira Clementino1, Patrícia Ferreira Neves da Luz1, Adriana Scavuzzi2, Carlos
Noronha Neto2, Melania Maria Ramos Amorim2
Medical Doctor of Obstetrics and Gynecology, Postgraduate Program on Maternal and Child Health, Professor Fernando Figueira Mother and Child Institute (IMIP), Recife, PE, Brazil
1
2
Professor of Obstetrics and Gynecology, Postgraduate Program on Maternal and Child Health, Professor Fernando Figueira Mother and Child Institute (IMIP), Recife, PE, Brazil
Summary
Study conducted at the Professor
Fernando Figueira Integral Medicine
Institute (IMIP), Recife, PE, Brazil
*Correspondence:
Address: Rua José Saretta, 155,
Nova Aliança
Ribeirão Preto, SP – Brazil
Phone: +55 16 9233-0662
[email protected]
http://dx.doi.org/10.1590/1806-9282.60.05.015
Objective: obtaining information on the factors associated with episiotomy will
be useful in sensitizing professionals to the need to minimize its incidence. Therefore, the objective of this study was to evaluate risk factors for episiotomy in
pregnant women who had undergone vaginal delivery at a university maternity
hospital in northeastern Brazil.
Methods: a case-control study was conducted with pregnant women submitted
to episiotomy (cases) and pregnant women not submitted to episiotomy (controls) between March 2009 and July 2010 at the Professor Fernando Figueira Integral Medicine Institute (IMIP) in Recife, Brazil, in a ratio of 1 case to 2 controls. The study variables consisted of: whether episiotomy was performed,
demographic, obstetric and fetal characteristics (primiparity, analgesia, instrumental delivery, fetal distress, etc.), external factors (day and time of delivery,
professional attending delivery) and factors directly related to delivery. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated. Multivariate
analysis was performed to determine the adjusted risk of episiotomy.
Results: a total of 522 women (173 cases and 349 controls) were included. It
was found that deliveries with episiotomy were more likely to have been attended by staff physicians (OR = 1.88; 95%CI: 1.01 - 3.48), to have required forceps
(OR = 12.31; 95%CI: 4.9 - 30.1) and to have occurred in primiparas (OR = 4.24;
95%CI: 2.61 - 6.89). The likelihood of a nurse having attended the delivery with
episiotomy was significantly lower (OR = 0.29; 95%CI: 0.16 - 0.55).
Conclusion: episiotomy was found to be strongly associated with deliveries attended by staff physicians, with primiparity, and with instrumental delivery, and
was less common in deliveries attended by nurses.
Keywords: episiotomy, natural childbirth, risk factors, perineum/injuries, case-control studies.
Introduction
Episiotomy, which consists in an incision on the perineum to widen the birth canal, was for a long time the principal procedure performed during childbirth. With the
objective of protecting the pelvic floor and preventing fetal trauma during birth, its routine use was widely accepted in the past, principally in primipara (woman in her
first labor and delivery).1
Nevertheless, a systematic review available in the Cochrane Library showed that episiotomy is not only a pro-
cedure that should not be performed routinely but also it
is both unnecessary and possibly harmful. That Cochrane
review included eight randomized clinical trials, involving
more than 5,000 women. Routine episiotomy was found
to be associated with greater blood loss during childbirth,
perineal pain, an increased risk of severe perineal laceration, a greater risk of scarring complications and a greater need for stitches, with no clearly demonstrated benefit
to the mother and/or infant. On the contrary, the authors
465
Braga GC et al.
concluded that the benefits of selective episiotomy (indicated under special circumstances) are much greater than
those found with routine episiotomy.2
Although the occasions in which a selective episiotomy should be performed are yet to be defined, publication of the results of controlled clinical trials and of the
Cochrane systematic review has led to a significant decline in the rates of this procedure.3,4 Since 1996, the World
Health Organization has stipulated an episiotomy rate
of around 10% as being acceptable,5,6 although the procedure continues to be performed routinely by a variety
of professionals in various countries.7
Evidence suggests a need for continued medical education and programs aimed at sensitizing the professionals involved in attending childbirth in order to reduce the use of this procedure.3,7,8 There is also a need to
document the factors associated with the use of episiotomy and to monitor the progressive reduction in its use
following introduction of a policy adopted to restrict its
practice.
Therefore, the present study was conducted with the
objective of describing the frequency of episiotomy in a
university maternity hospital in the Northeast of Brazil
and identifying the principal factors associated with the
procedure.
Methods
An analytical, observational, case-control study was conducted with women who had undergone vaginal delivery
at the (IMIP) in Recife, Pernambuco, Brazil. The study
was conducted between March 2009 and July 2010 following approval by the institution’s internal review board (reference #1284-08). All the women voluntarily agreed to participate in the study and signed an informed consent form.
Sample size was calculated using the Statcalc module of the Epi-Info program, version 3.5.3. (Atlanta, GA,
USA). Considering a frequency of forceps delivery without episiotomy of 1% and an odds ratio (OR) of 7.0 9 for
a case to control ratio of 1:2, 173 cases and 349 controls
would be required to show a difference, making a total of
522 women.
A consecutive convenience sample was obtained, consisting of all the women who fulfilled the eligibility criteria and who were in the maternity ward when the investigators made their visits every other day, during the day
shift. The women were interviewed immediately following delivery, prior to their release from hospital. The inclusion criterion was having had an assisted vaginal de-
livery at IMIP. Women who had been submitted to
episiotomy were considered cases, while those who had
not undergone episiotomy were admitted as controls.
Women unable to give their informed consent (those in
a coma, unconscious or mentally retarded) and who did
not have an accompanying person with them who could
consent to their participation in the study on their behalf were excluded from the study.
The dependent variable was having undergone episiotomy in any form (mediolateral or midline) and the independent variables were: a) maternal variables: age (years),
parity, ethnicity (brown, black, white, yellow or indigenous),
nutritional status evaluated according to body mass index
(BMI), sociodemographic characteristics (place of origin
and years of schooling); b) complications of pregnancy
(diseases inherent to pregnancy or occurring during pregnancy), gestational age at delivery (weeks), previous Cesarean section, previous episiotomy; c) fetal characteristics:
fetal presentation and fetal position during labor; d) external factors: the work shift, the professional attending delivery and the time of delivery; e) direct factors (related to
delivery): induction or conduction of delivery, position at
delivery (supine or other), type of delivery (spontaneous or
instrumental), duration of expulsive phase, use of analgesia during delivery, presence of non-reassuring fetal heart
rate, shoulder dystocia and fetal macrosomia.
The data were collected on standardized forms precoded for computer data entry. The statistical analysis
was performed using the publicly available Epi-Info software program, version 7 (Atlanta, GA, USA). Measures
of central tendency and dispersion and frequency distribution were used to describe the baseline characteristics. To determine the association between the dependent variable (episiotomy) and the independent variables
(predictors), the chi-square test of association and Fisher’s exact test were used, as appropriate, at a 5% significance level. The odds ratios (OR) and 95% confidence
intervals (95%CI) were calculated. Multivariate analysis was carried out following a model of hierarchical
multiple logistic regression 10 to determine the adjusted risk of episiotomy.
Results
During the study period, 2,563 vaginal deliveries were
performed in the institute, with a frequency of episiotomy at around 10% (259 cases). Of these, 542 women
were approached and 522 women agreed to participate
in the study: 173 cases and 349 controls (Figure 1).
weeks). Complications had occurred during pregnancy
in around 52% of the participants, with a frequency of
hypertensive syndromes of approximately 35%. Induction of labor with oxytocin was required in 55% of the
women and 9.4% were submitted to instrumental delivery with the use of forceps (Table 1).
Total number of vaginal deliveries in IMIP
2,563
With episiotomy
259
Without episiotomy
2,304
Table 1 Baseline characteristics of the participants
ELIGIBILITY
CRITERIA
Considered for participation
= 180
Agreed to participate
= 173 (Cases)
(n = 522)
Characteristic
Considered for participation
= 362
Agreed to participate
= 349 (Controls)
Age (range. mean ± SD)
13 – 44
23.9 ± 6
Previous pregnancies (range. median)
1 – 15
1
Previous deliveries (range. median)
1 – 12
1
Primiparas (n. %)
322
61.7
Schooling
Figure 1 Flow chart of the study.
< 8 years of schooling
148
28.4
≥ 8 years of schooling
373
71.6
Recife
234
44.9%
Other towns
288
55.2
Place of origin
The age of the women ranged from 13 to 44 years, with
a mean of around 24 years of age. The median number
of previous pregnancies and deliveries was 1, with a percentage of primiparas of 61.7%. The majority of the women (72%) had at least eight years of schooling and 45%
came from the city of Recife. Mean gestational age at delivery was 37.6 weeks, with 29.5% of prematurity (< 37
Gestational age at delivery (range. mean ± SD) 23 – 42 37.6 ± 2.9
Prematurity (n. %)
154
29.5
Complications in pregnancy
272
52.1%
Hypertensive syndromes
182
34.9%
Delivery induced (n. %)
286
54.8%
Instrumental delivery (n. %)
49
9.4%
Table 2 Maternal and fetal factors associated with the use of episiotomy
Episiotomy
Associated factors
OR
95%CI
p-value
20.9
2.22
1.48 – 3.32
0.00009
178
51
3.08
2.16 – 4.41
0.0000000
9.8
53
15.2
0.61
0.34 – 1.09
0.09
41
23.7
110
31.5
0.67
0.44 – 1.02
0.06
< 8 years of schooling
38
22
110
31.5
0.61
0.4 – 0.94
0.02
Lives in Recife
70
40.5
164
59.5
0.77
0.65 – 1.07
0.16
Prematurity
51
29.5
122
47
1
0.76 – 1.3
0.99
Complications during pregnancy
98
56.6
174
49.9
1.31
0.94 – 1.54
0.14
Previous cesarean section
9
5.2
20
5.7
0.9
0.4 – 2.03
0.8
Yes = 173
No = 349
n
%
n
%
Maternal age < 20 years
64
37
63
Primiparity
144
83.2
Black skin color
17
Overweight/obese
Previous episiotomy
16
9.2
97
27.8
0.26
0.15 – 0.47
0.000002
Pelvic presentation
4
2.3
2
0.6
4.11
0.74 – 22.64
0.19*
Occipito-posterior position
22
28.6
41
36.9
0.68
0.36 – 1.28
0.23
95%CI: 95% confidence interval; OR: Odds Ratio.
* Fisher’s exact test (two-tailed).
467
Braga GC et al.
Analysis of the maternal risk factors showed that the women submitted to episiotomy were more likely to be adolescents (OR = 2.22; 95%CI: 1.48 – 3.32) and primiparas
(OR = 3.08; 95%CI: 2.16 – 4.41) and less likely to have fewer than eight years of schooling (OR = 0.61; 95%CI: 0.40
– 0.94) or a history of having had a previous episiotomy
(OR = 0.26; 95%CI: 0.15 – 0.47). There was no association
between episiotomy and the presence of complications
during pregnancy (p = 0.14), overweight/obesity (p = 0.06),
being black (p = 0.09), coming from Recife (p = 0.16), prematurity (p = 0.99) or having had a previous Cesarean section (p = 0.80). In relation to fetal risk factors, no association was found between episiotomy and pelvic presentation
(p = 0.19) or occiput posterior fetal position during labor
(p = 0.23) (Table 2).
With respect to the factors directly related to care at
delivery, the women submitted to episiotomy were more
likely to have had labor induced with oxytocin (OR = 1.92;
95%CI: 1.31 – 2.79), an instrumental delivery (OR = 18.91;
95%CI: 7.86 – 45.48), a prolonged expulsive phase (12%
versus 0%, OR not calculated, p<0.000001), analgesia during labor (OR = 3.0; 95%CI: 1.77 – 5.08) and a diagnosis
of non-reassuring fetal heart rate (OR = 3.4; 95%CI: 1.82
– 6.37). There was no association between episiotomy and
delivery in the supine position (p = 0.05) or fetal macrosomia (p = 0.52) (Table 3).
Regarding the external factors evaluated, the women submitted to episiotomy were three times more likely to have been attended by a staff physician (OR = 3.36;
95% CI: 1.97 – 5.72). On the other hand, delivery attended by nurses or resident nurses was found to constitute a protective factor against episiotomy (OR =
0.19; 95% CI: 0.10 – 0.35). There was no association
between episiotomy and the day of the week or work
shift (Table 3).
When multivariate analysis was performed using a
hierarchical logistic regression model, the factors that remained significantly associated with a greater risk of episiotomy were primiparity (OR = 4.24; 95%CI: 2.61 – 6.89),
instrumental delivery (OR = 12.31; 95%CI: 4.9 – 30.81)
and delivery attended by a staff physician (OR = 1.88;
95%CI: 1.01 – 3.48), whereas a reduction in the risk was
found when delivery was attended by a nurse (OR = 0.24;
95%CI: 0.16 – 0.55) (Table 4).
Table 3 Intrapartum and external factors associated with the use of episiotomy
Episiotomy
Associated factors
OR
95% CI
p-value
49.6
1.92
1.31 – 2.79
0.0007
195
55.9
0.69
0.48 – 1
0.05
24.9
6
1.7
18.91
7.86 – 45.48
0.00000000
22
12
0
0
NE*
NE*
0.00000000
Analgesia at delivery
37
21.4
29
8.3
3
1.77 – 5.08
0.00002
Fetal distress
27
15.6
18
5.2
3.4
1.82 – 6.37
0.00006
Fetal macrosomia
5
2.9
9
2.6
1.12
0.37 – 3.41
>0.999999*
Sunday shift
33
19.1
46
13.2
1.32
0.98 – 1.77
0.08
Tuesday shift
18
10.4
44
12.6
0.81
0.45 – 1.44
0.23
Night shift
88
50.9
175
50.1
1.03
0.71 – 1.48
0.88
Delivery attended by medical staff
38
22
27
7.7
3.36
1.97 – 5.72
0.000005
Delivery attended by nurse or resident nurse
14
8.1
109
31.2
0.19
0.1 – 0.35
0.0000000
Yes = 173
No = 349
n
%
n
%
Induction of delivery
113
65.3
173
Supine position
81
46.8
Instrumental delivery
43
Prolonged expulsive phase
95%CI: 95% confidence interval; OR: Odds Ratio; NE= Not estimated.
* Fisher’s exact test.
Table 4 Multivariate analysis of the principal factors associated with episiotomy
Variable
Odds Ratio
95%CI
Delivery attended by nurse
0.29
0.16 – 0.55
Instrumental delivery
12.31
Primiparity
Delivery attended by staff physician
Standard Error
p-value
-1.2248
0.32
0.0001
4.9 – 30.81
2.5101
0.47
0.0000
4.24
2.61 – 6.89
1.4441
0.25
0.0000
1.88
1.01 – 3.48
0.6292
0.31
0.0457
-1.7816
0.22
0.0000
Constant
Coefficient
Discussion
The results of the present study suggest that the most important factors associated with episiotomy at IMIP are:
primiparity, delivery attended by a staff physician and the
use of forceps. In the case of women in whom episiotomy was not performed, their delivery was more likely to
have been attended by nurses.
There was a 4-fold greater likelihood of episiotomy
having been performed in primiparas. These results are in
agreement with findings reported in the literature. One
study conducted in the United States including 8,647 patients showed a frequency of episiotomy of 50% in primiparas compared to 23% in secundiparas and multiparas, a
difference that was statistically significant.11 Nevertheless,
these data may reflect a more liberal practice of episiotomy in primiparas rather than any real need for the procedure in this group of women.
A clinical trial conducted in Venezuela showed no advantage in the routine use of episiotomy in primiparas 12
and the subgroup analysis in a Cochrane systematic review
also did not favor the practice of episiotomy in primiparous
women 2. A large population-based, retrospective study including 2,315 primiparas and 534 multiparas concluded
that episiotomy protected primiparas but not multiparas
from the risk of an anal sphincter lesion; however, the indications for performing this procedure should be restricted,
since 909 episiotomies would have to be performed to avoid
one single case of anal sphincter rupture.13
The association found in the present study between
fewer episiotomies and obstetric care provided by nurses
was not surprising. In the systematic review available in
the Cochrane Library, the risk of episiotomy was 20% lower in deliveries attended by midwives (20.7% versus 25.1%).14
In the present study, the risk was much smaller, since fewer than 8% of deliveries in which episiotomy was performed were attended by nurses, while almost 30% were
attended by physicians.
It could perhaps be argued that episiotomy is less likely to be performed by non-physicians because these pro-
fessionals only attend low-risk deliveries in which there is
less need for episiotomy. Nevertheless, this explanation is
not supported by the results of the present study, since a
multivariate analysis was conducted and even after controlling for potentially confounding variables such as complications during pregnancy, a prolonged expulsive phase
and instrumental delivery, deliveries at which episiotomy
was performed were much less likely to have been attended by obstetric nurses. It is important to clarify that in the
northeast of Brazil there are no university courses for midwives, which is why these professionals are not included in
the childbirth care model used in this setting.
The important association between episiotomy and
deliveries attended by staff physicians, but not those attended by medical residents, suggests that this procedure
is strongly related to the amount of time the professional
has been working in the area, since young medical residents are less likely to perform episiotomy. It is important
to remember that the training of these new professionals
is based on scientific evidence at a time in which the systematic practice of episiotomy in obstetrics is already being questioned. Deliveries involving episiotomy are almost
twice as likely to have been attended by physician preceptors, many of whom graduated at a time in which the routine practice of episiotomy was not questioned.
As evidence accumulates on the lack of benefits of
routinely performing episiotomy, we believe that young
doctors will easily incorporate their critical judgment of
this procedure into their clinical practice, unlike the physician preceptors who, despite the available evidence, are
resistant to changes in conduct.
The association between episiotomy and forceps assisted deliveries was most evident in the present study,
with a more than 12-fold likelihood of deliveries with
an episiotomy having involved the use of forceps. It
should be emphasized that the use of forceps or vacuum extraction used to be considered a classic indication
for episiotomy. However, in addition to there being no
469
Braga GC et al.
clear indication for episiotomy when an instrumental
delivery is performed, the combination of an instrumental delivery and an episiotomy is believed to result in an
increase in severe lacerations of the perineum, with possible damage to anal function. Recent studies recommend that this combination be avoided.14-16 Even so,
many professionals continue to believe that instrumental delivery constitutes an indication for episiotomy.
Indeed, it is rather unclear in which situations episiotomy is in fact indispensable. The Cochrane systematic review raised the question regarding the real
indications for this procedure: operative vaginal delivery, preterm delivery, pelvic delivery, macrosomia or
the risk of severe perineal laceration.2 Consequently,
a debate has ensued on whether these situations constitute indicators of a need for episiotomy and clearly
require to be investigated further in new randomized
clinical trials.17
With the objective of studying the factors that may
affect whether or not this procedure is performed, in addition to the variables already mentioned, the present
study also evaluated other factors such as pelvic presentation, prematurity, previous Cesarean section, non-reassuring heart rate, previous episiotomy, complications during pregnancy, macrosomia, induction of labor and/or
the use of oxytocin during labor, and the use of analgesia during childbirth.
It was impossible to evaluate the association between
episiotomy, shoulder dystocia, pelvic presentation and
the diagnosis of a “risk of severe perineal laceration.”
Shoulder dystocia occurred in one single case and was
not included as a variable in the analysis. Pelvic presentation occurred in six cases; however, there was no statistically significant association with episiotomy. On the
other hand, “risk of severe perineal laceration” was not
recorded on the women’s medical charts as an indication
for performing episiotomy, perhaps because this diagnosis is subjective. It is possible that some physicians may
have performed episiotomy to protect the perineum
against this risk of severe perineal laceration; however,
there was no record of this indication on the medical
charts. It should be emphasized that “risk of severe perineal laceration” is not an objective diagnosis and, clinically, the factors that characterize this event are not well
defined.2, 17
Although various authors have mentioned prematurity as an indication for episiotomy, with the objective of
protecting the head of the fetus, in the present study no
such association was found. Indeed, there are no clinical
trials or observational studies corroborating the need for
episiotomy in premature deliveries or any evidence justifying the use of episiotomy to prevent fetal trauma at delivery.1, 2, 17 On the contrary, a study evaluating 1,360 nulliparas submitted to forceps delivery or vacuum extraction
showed that the use of episiotomy was associated with
an increase in the rate of fetal contusions and skin abrasions, while having no effect on neonatal outcomes such
as Apgar score, fetal acidosis or admission to a neonatal
intensive care unit.15
History of a previous Cesarean section, characterizing
a woman who has not yet delivered vaginally, was not associated with any increase in the risk of having an episiotomy, contrary to the findings of another study carried out
in Pernambuco, Brazil.18 On the other hand, having had
a previous episiotomy was found to have a protective effect in the bivariate analysis, although this association was
no longer present in the multivariate analysis.
Although the diagnosis of “non-reassuring heart rate”
was associated with a greater risk of episiotomy in the bivariate analysis, this risk also failed to remain significant
in the multivariate analysis. The intention of shortening
the expulsive phase in cases in which anomalous fetal heart
rate patterns are detected may have led some physicians to
perform episiotomy. Another possible explanation is that
when faced with a situation in which fetal vitality is compromised, some professionals may have opted to use forceps, and the majority of obstetricians still believe, as discussed previously, that episiotomy is fundamental when
performing an instrumental delivery.1, 14-17
With respect to macrosomia (fetal birth weight ≥ 4
kg) no statistically significant association was found with
the practice of episiotomy. This fact may have occurred
as a result of the obstetricians having no information on
the weight of the concept prior to delivery. It should be
emphasized that it is not routine practice in this service
to perform ultrasonography at term for the purpose of
predicting fetal weight, since the accuracy of this exam
in detecting macrosomia is poor.19,20 At any rate, studies
suggest that episiotomy is not recommended either for
the delivery of macrosomic fetuses or in situations in
which shoulder dystocia occurs.17, 21 In fact, recent evidence shows that, even in the presence of conditions classically considered as “indications” for an episiotomy (macrosomia, non-reassuring heart rate, occipito-posterior
position, shoulder dystocia and instrumental delivery),
the risk of third and fourth degree lacerations was significantly greater when episiotomy was performed.22
In the bivariate analysis, both analgesia at delivery and
induction with oxytocin were associated with episiotomy,
although this association was no longer present in the mul-
tivariate analysis. There does not appear to be any direct
association between the use of drugs to induce delivery or
to provide analgesia and a need for an episiotomy; however, the presence of these variables may indicate a more interventionist approach by the professional attending delivery. Induced deliveries may also be more dystocic and
may trigger a cascade of other interventions 23. On the other hand, some professionals may find it simpler to perform
an episiotomy in patients under analgesia; however, this
may also lead to an increase in the duration of the expulsive phase and a greater risk of an instrumental delivery in
patients receiving epidural analgesia.24
No association was found between episiotomy and
complications such as preeclampsia, hypertension, diabetes and other conditions during pregnancy that would
characterize it as high-risk. We believe that the presence
of these factors may increase the risk of a Cesarean section, but they do not appear to affect the clinical decision
to perform an episiotomy.
In relation to the position of the woman at delivery,
positions other than the supine position (upright, lateral or hands-and-knees position) were less common in the
group submitted to episiotomy (47% versus 56%), which
is in agreement with the Cochrane systematic review suggesting that the risk of episiotomy is lower in non-supine
positions.25 Nevertheless, the association between the
woman’s position at delivery and episiotomy did not remain statistically significant in the multivariate analysis,
probably because more important factors such as the professional attending the delivery were associated both with
the choice of the woman’s position for delivery and with
the practice of episiotomy.
The rate of episiotomy at IMIP has fallen progressively over recent years and is currently at around 10%. Nevertheless, we believe that this rate can still be improved significantly, since most of the factors shown in the present
study to be associated with the use of episiotomy are potentially modifiable. Stimulating care by nursing professionals at low-risk deliveries is fully possible and a measure
that is recommended worldwide.14 On the other hand, we
believe that all the efforts made in the institute towards
forming a new generation of physicians within a paradigm
of evidence-based medicine have resulted in success, with
a new generation of medical residents that has incorporated the concept that routine episiotomy is unnecessary.
For the future, we would suggest broadening the discussion on the actual indications for episiotomy and questioning the true role of episiotomy in pelvic and instrumental deliveries. Some authors have suggested that episiotomy
may not be absolutely necessary in childbirth.17, 22
Until the results of these future clinical trials become
available, we suggest that efforts be made to restrict the
practice of episiotomy and maintain rates within the limits suggested by the World Health Organization, i.e. 10%
of deliveries. Both in individual and in institutional practice, it is important to document episiotomy rates and to
recognize the factors associated with its practice in order
to elaborate strategies to prevent unnecessary procedures
that, in addition to being unwanted by women, may indeed be harmful to their health.2, 3, 5-8
Funding
National Council for Scientific and Technological Development (CNPq). Scientific initiation grant.
Resumo
Fatores de risco para a episiotomia: um estudo de caso-controle.
Objetivo: avaliar os fatores de risco para a episiotomia em
mulheres grávidas que passaram por parto normal em uma
maternidade de uma universidade no nordeste do Brasil.
Métodos: um estudo de caso-controle foi realizado com
gestantes submetidas à episiotomia (casos) e mulheres
grávidas não submetidas à episiotomia (controles) entre
março de 2009 e julho de 2010, no Instituto de Medicina Integral Fernando Figueira (IMIP), Recife, Brasil, em
uma proporção de um caso para dois controles. As variáveis do estudo foram: se episiotomia foi realizada, demográficos, obstétricos e características fetais (primiparidade, analgesia, parto instrumental, sofrimento fetal, etc.),
fatores externos (dia e hora do parto, profissional que realizou o parto) e fatores diretamente relacionados ao parto. Odds ratio (OR) e intervalos de confiança de 95% (IC
95%) foram calculados. A análise multivariada foi realizada para determinar o risco ajustado de episiotomia.
Resultados: um total de 522 mulheres (173 casos e 349
controles) foi incluído. Verificou-se que os partos com
episiotomia eram mais propensos a ter sido atendidos
por médicos do staff (OR = 1,88, IC 95%: 1,01 - 3,48), necessidade de fórceps (OR = 12,31, IC 95%: 4,9 - 30,1) e ter
ocorrido em primíparas (OR = 4,24, 95% CI: 2,61 - 6,89).
A probabilidade de uma enfermeira ter assistido o parto
com realização de episiotomia foi significativamente menor (OR = 0,29, 95% CI: 0,16 - 0,55).
Conclusão: a episiotomia foi considerada fortemente associada a partos assistidos por médicos da equipe, primiparidade e a parto instrumental, e foi menos comum em
partos assistidos por enfermeiros.
471
Braga GC et al.
Palavras-chave: episiotomia, parto normal, fatores de
risco, períneo/lesões, estudos de casos e controles.
References
1. Myers-Helfgott MG, Helfgott AW. Routine use of episiotomy in modern
obstetrics. Should it be performed? Obstet Gynecol Clin North Am.
1999;26:305-25.
2. Carroli G, Mignini L. Episiotomy for vaginal birth. Cochrane Database Syst
Rev. 2009;(1):CD000081.
3. Eckman A, Ramanah R, Gannard E, Clement MC, Collet G, Courtois L, et
al. [Evaluating a policy of restrictive episiotomy before and after practice
guidelines by the French College of Obstetricians and Gynecologists]. J
Gynecol Obstet Biol Reprod (Paris). 2010;39:37-42.
4. Levitt C, Hanvey L, Bartholomew S, Kaczorowski J, Chalmers B, Heaman
M, et al. Maternity Experiences Study Group; Public Health Agency of Canada.
Use of routine interventions in labour and birth in Canadian hospitals:
comparing results of the 1993 and 2007 Canadian hospital maternity policies
and practices surveys. J Obstet Gynaecol Can. 2011;33:1208-17.
5. World Health Organization. Maternal and newborn health/safe motherhood
unit. Care in normal birth: a practical guide. Geneva: WHO; 1996.
6. World Health Organization. Managing complications in pregnancy and
childbirth. A guide for midwives and doctors. Geneva: WHO Department
of Reproductive Health and Research; 2003.
7. Faruel-Fosse H, Vendittelli F. [Can we reduce the episiotomy rate?]. J Gynecol
Obstet Biol Reprod. (Paris) 2006;35(1 Suppl):1S68-1S76.
8. Goldberg J, Purfield P, Roberts N, Lupinacci P, Fagan M, Hyslop T. The
Philadelphia Episiotomy Intervention Study. J Reprod Med. 2006;51:603-9.
9. Allen RE, Hanson RW Jr. Episiotomy in low-risk vaginal deliveries. J Am
Board Fam Pract. 2005;18:8-12.
10. Victora CG, Huttly SR, Fuchs SC, Olinto MT. The role of conceptual
frameworks in epidemiological analysis: a hierarchical approach. Int J
Epidemiol. 1997;26:224-7.
11. Hueston WJ. Factors associated with the use of episiotomy during vaginal
delivery. Obstet Gynecol. 1996;87:1001-5.
12. Rodriguez A, Arenas EA, Osorio AL, Mendez O, Zuleta JJ. Selective vs routine
midline episiotomy for the prevention of third- or fourth-degree lacerations
in nulliparous women. Am J Obstet Gynecol. 2008;198:285.e1-4.
13. Räisänen SH, Vehviläinen-Julkunen K, Gissler M, Heinonen S. Lateral
episiotomy protects primiparous but not multiparous women from obstetric
anal sphincter rupture. Acta Obstet Gynecol Scand. 2009;88:1365-72.
14. Hatem M, Sandall J, Devane D, Soltani H, Gates S. Midwife-led versus other
models of care for childbearing women. Cochrane Database Syst Rev.
2008;(4):CD004667.
15. Macleod M, Strachan B, Bahl R, Howarth L, Goyder K, Van de Venne M, et
al. A prospective cohort study of maternal and neonatal morbidity in relation
to use of episiotomy at operative vaginal delivery. BJOG. 2008;115:1688-94.
16. Yeomans ER. Operative vaginal delivery. Obstet Gynecol. 2010;115:645-53.
17. Amorim MMR, Katz, L. [The role of episiotomy in modern obstetrics].
Femina. 2008;36:47-54.
18. Carvalho CCM, Souza ASR, Moraes Filho OB. [Prevalence and factors
associated with the practice of episiotomy at a maternity school in Recife,
Pernambuco, Brazil]. Rev Assoc Med Bras. 2010;56:333-9.
19. Coomarasamy A, Connock M, Thornton J, Khan KS. Accuracy of ultrasound
biometry in the prediction of macrosomia: a systematic quantitative review.
BJOG 2005;112:1461-6.
20. Colman A, Maharaj D, Hutton J, Tuohy J. Reliability of ultrasound estimation
of fetal weight in term singleton pregnancies. N Z Med J. 2006;119:U2146.
21. Paris AE, Greenberg JA, Ecker JL, McElrath TF. Is an episiotomy necessary
with a shoulder dystocia? Am J Obstet Gynecol.2011;205:217.e1-3.
22. Steiner N, Weintraub AY, Wiznitzer A, Sergienko R, Sheiner E. Episiotomy:
the final cut ? Arch Gynecol Obstet. 2012;286:1369-73.
23. Tracy SK, Sullivan E, Wang YA, Black D, Tracy M. Birth outcomes associated
with interventions in labour amongst low risk women: a population-based
study. Women Birth. 2007;20:41-8.
24. Anim-Somuah M, Smyth RM, Jones L. Epidural versus non-epidural or no
analgesia in labour. Cochrane Database Syst Rev. 2011;(12):CD000331.
25. Gupta JK, Hofmeyer GJ, Shehmar M. Position in the second stage of labour
for women without epidural anaesthesia. Cochrane Database Syst Rev.
2012;5:CD002006.
original article
Rafael Barberena Moraes1*, Andréia Della Giustina2, Eliana Madalena Vicentini Farenzena2, Laura de Mattos Milman2,
Renata Sehbe Fedrizzi2
PhD and MSc in Endocrinology- UFRGS; Instructor, Department of Internal Medicine at Hospital Nossa Senhora da Conceição; Intensive care specialist at the Hospital de Clínicas de Porto Alegre and Fêmina Hospital;
1
Specialist in Intensive Care from the AMIB, Medical Residency Program.
2
Resident in Internal Medicine, Hospital Nossa Senhora da Conceição.
Summary
Study conducted at Hospital Nossa
Senhora da Conceição
Article recieved: 15/10/2013
*Correspondence
Address: Rua Erechim, 100/31
Porto Alegre, RS – Brazil
Phone/Fax: +55 51 30280591
[email protected]
Financial support: GEP- GHC: Teaching
and Research Management Department
Grupo Hospitalar Conceição.
http://dx.doi.org/10.1590/1806-9282.60.05.016
Objective: according to the epidemiologic and antimicrobial resistance profile,
infections are usually classified as community-acquired or nosocomial. Reports
on patients without the classic criteria for nosocomial infection with multidrug-resistant germs are increasing. There is a particular concern regarding which microbiological profile must be addressed in case of infections in healthcare workers. This study was carried out with the purpose of identifying the prevalence
of infection by multidrug-resistant germs in healthcare workers exposed to occupational contact with such germs at work.
Methods: observational and retrospective study. In a 7-year period, healthcare
worker hospitalizations were identified and the cultures results were assessed in
order to identify the prevalence of infection by multidrug-resistant pathogens.
Results: 1,487 healthcare workers hospitalizations were identified. In 105 of these hospitalizations, cultures were collected on the first 5 days after admission,
and in 22 patients, 24 germs were identified. Multidrug-resistant pathogens were
not found.
Conclusion: in our sample, composed of workers from a tertiary public hospital who were hospitalized, none of the individuals presented MDR colonization
or infection. These results suggest that when healthcare workers present infections, they must receive antibiotic therapy directed to community-acquired pathogens. In light of the limitations of this study, further larger and multicenter
studies must be developed to enlighten such issue.
Keywords: nosocomial infection, antibacterial resistance, community-acquired infection, healthcare workers.
Introduction
Knowing the colonization profile of the population addressed is crucial to determine an empirical antibiotic therapy to be employed.1,2 Historically, infections are defined
as community-acquired (patients from extra-hospital setting) or nosocomial (acquired after at least 48 hours of admission or due to it), and empirical therapy is based on the
germs commonly involved in each situation. More recently, the literature has used the expression “healthcare-associated infections”3,4 to designate infections caused by
multidrug-resistant organisms in outpatients with risk factors and exposure to MDRs, including those residing in
nursing homes, or who had extended contact with intrahospital or hemodialysis facilities in the past 30 days, required hospitalization in emergency units for a period exceeding 48 hours in the last 90 days, or who underwent
intravenous therapies in past 30 days.2-4
Recent reports have associated exposure to hospital
germs to the development of infections by these pathogens. Thus, health professionals as well as patients with
“infections associated with healthcare”, even without hospital admission, would be prone to colonization or infection with these germs. Because of that, it is argued which
473
Moraes RB et al.
single empirical antibiotic therapy would be correct in
case of infection in a healthcare worker: empirical coverage directed to community germs or MDR bacteria?5-8
Based on that, defining the colonization profile of
healthcare workers is a matter of great importance and
aims to avoid prescription of inadequate empirical antibiotic therapy, which is associated with increased morbidity and mortality (if using limited spectrum antibiotic
medication to treat patients with MDR bacteria), as well
as the development of antimicrobial resistance within the
population and unnecessary hospitalizations (in cases of
improper use of broad-spectrum antibiotics).9-12 To corroborate the elucidation of this question, we developed
this retrospective observational study aimed to identify
the microbiological profile of infections in healthcare
professionals who required hospitalization.
Methods
An observational study was conducted through search of
electronic medical charts at the Nossa Senhora da Conceição Hospital (HNSC), located in Porto Alegre, state of Rio
Grande do Sul, Brazil. Admissions of employees of the Conceição Hospital Group (GHC), which includes the Nossa
Senhora da Conceição Hospital, Cristo Redentor Hospital, Fêmina Hospital, and the Conceição Children’s Hospital, were identified retrospectively. The GHC is composed of tertiary level hospitals with endemic rates of
colonization with MDR bacteria. All hospitalizations occurred at the Nossa Senhora da Conceição, since this is the
hospital for clinical admissions in the GHC.
The population enrolled included workers of the GHC,
admitted to the Nossa Senhora da Conceição Hospital
in the period from January 2005 to January 2012, identified by means of their punch-in cards, regardless of the
reason for hospitalization. Of these, patients with risk
factors for colonization that did not arise from work activities were excluded: previous hospitalization for less
than six months, with cultures collected after the fifth
day of hospitalization, or with the absence of cultures.
Data collection was initiated once the project was approved by the Research Ethics Committee-GHC, being performed from April to October 2012. The information was
collected using searches for the following variables: gender, age, occupation (physician, nurse, nursing assistant/
technician, or positions with no direct contact with patients), comorbidities, reason for hospitalization, ICU admission, and type outcome (hospital discharge vs. death).
Contact with MDR bacteria was defined based on occupation and sector of activity. Doctors, nurses or nursing
technicians who worked in areas with high rates of infec-
tion or colonization with MDR bacteria, such as emergency
rooms, ICUs, recovery rooms and wards, were regarded as
professionals in contact with MDRs. Professionals who
did not work in these sectors or who worked in these sectors performing activities without direct patient contact
were considered as workers not in contact with MDRs. The
reason for admission was classified as infectious or non-infectious and, in the case of infection, its focus was established. Patients with positive cultures who did not receive antibiotic treatment, on account of being asymptomatic
despite bacterial growth on culture or whose medical charts
did not mention infection, were defined as colonized patients (carriers). Empirical antibiotic therapy was considered adequate if the bacteria were sensitive to the antibiotic
used. De-escalation of antimicrobial treatment after culture results was also assessed. Research sources were the
admission form, the hospital discharge form and the outpatient consultation charts kept electronically by the hospital. The first chest radiography on admission was assessed. The chest X-ray was classified as compatible or not
with bronchopneumonia, being compatible in case of new
lobar consolidation, interstitial infiltrates or cavitating lesions. To define multidrug-resistant germs, we adopted
the definition of ESKAPE pathogens previously created to
emphasize the pathogens that most often correlate with
hospital infections and that “escape” the effects of antibacterial drugs. They include: Vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, Klebsiella species and ESBL-producing Escherichia coli, Acinetobacter
baumannii, Pseudomonas aeruginosa and extended spectrum
beta-lactamase (ESBL)- or carbapenemase-producing Enterobacteriaceae.13 Importantly, the data were subjected to total secrecy, not allowing the identification of patients/staff.
Since this was a retrospective chart review, no consent form
was applied, as approved by the local ethics committee.
Statistical analysis was performed with SPSS 17.0
software (statistical package software, SPSS Incorporation, Chicago, IL, USA). The X2 was used to evaluate categorical variables and Student’s t test for parametric continuous variables. For sample size calculation, the
prevalence of positive cultures in 50% of the hospitalizations was estimated with a confidence level of 90%, being
thus required the identification of 97 admissions.
Results
1,487 admissions of health workers were assessed in the
study. In 1,155, there was no culture collection in the first
five days of hospitalization, and in 227, the employee had
already been hospitalized in the past six months. Of the
105 admissions with cultures collected in the first five
days, 83 were negative, and 22 hospitalizations had 24
bacteria isolated (Table 1 and Figure 1): Escherichia coli
(10), Coagulase-negative staphylococci (CoNS,5), Klebsiella
pneumoniae (2) and 7 other germs: Enterococcus faecium, Enterococcus faecalis (both sensitive to ampicillin), Serratia
marcescens, Staphylococcus epidermidis (oxacillin susceptible), Pseudomonas aeruginosa (sensitive to quinolones, cefepime, piperacillin-tazobactam and carbapenems), Streptococcus agalactiae and Cryptococcus neoformans. Multiresistant
bacteria were not isolated from any employee.
The profile of the sample is shown in Table 1. Among
the 22 patients, 10 (45.5%) were nursing technicians and
12 (54.5%) had positions without direct patient contact:
supervisors, administrative technicians, elevator operators, nutrition attendants, managers, pharmacy assistants,
biomedical technicians, dispensers and cast technicians.
There were no physicians or nurses in the sample. Based
on workplace and job function, 10 employees had possible contact with MDR bacteria, 11 had no contact and 1
(4.5%) could not be determined.
Of the 22 admissions with bacterial isolates, 15 (68.2%)
were hospitalizations due to infectious causes and 7
(31.8%), non-infectious. Thirteen patients received antibiotics. In 8 patients, the initial antibiotic therapy was
considered appropriate to the pathogen, being maintained in 5 cases and de-escalated in 3, according to antibiogram. In the other 2 patients, antibiotics were initiated
after culture results. Among the 3 hospitalizations in
which he empirical antibiotic therapy was considered
inappropriate, one had the antibiotic therapy discontinued once the infection was attributed to cryptococcal meningitis, and in 2 the antibiotic therapy was adjusted after
culture results (amoxicillin-clavulanate was replaced by piperacillin-tazobactam and metronidazole was replaced by cephalothin). The bacteria isolated in these cultures were
Pseudomonas aeruginosa and Staphylococcus epidermidis, respectively. In the other 9 hospitalizations, antibiotics were
not used because they were considered cases of colonization or sample contamination.
In this study, MDR bacteria were not found among
the 24 cultures isolated from biological material taken
from 22 employees of a general hospital. It is essential to
point out that ten of these employees worked in areas
with endemic presence of MDR bacteria. Reports prepared by the Commission of Hospital Infection at the Nossa Senhora da Conceição Hospital highlight the high pre-
Table 1 Patient profile (n = 22)
Results
Age (years)
49.3 ± 10.6
Gender (F/M)
13 (59%) / 9 (41%)
Comorbidities
- Congestive heart failure
1 (4.5%)
- High blood pressure
7 (32%)
- Chronic obstructive pulmonary disease
1 (4.5%)
- Smoking
6 (27%)
- Diabetes mellitus
2 (9%)
- Acute renal failure requiring dialysis
1 (4.5%)
- Tuberculosis
2 (9%)
- Depression
3 (13.5%)
- Acquired immunodeficiency syndrome
1 (4.5%)
- Neoplasm
5 (23%)
Occupation
- Nurse technician
10 ( 45%)
- Other positions
12 (55%)
Microorganisms isolated
- Escherichia coli
10 (42%)
- Coagulase-negative staphylococci
5 (21%)
- Klebsiella pneumoniae
2 (8%)
- Other
7 (29%)
Source of microorganism isolates
- Blood cultures
7 (31.8%)
- Urocultures
10 (45.5%)
- Sputum
1 (4.5%)
- Cerebrospinal fluid
1 (4.5%)
- Cutaneous abscess
1 (4.5%)
- Pulmonary lymph node
1 (4.5%)
- Abdominal fluid
1 (4.5%)
Origin
- Respiratory
8 (36.4 %)
- Abdominal
3 (13.6%)
- Urinary
9 (40.9%)
- Cutaneous
1 (4.5%)
- Central nervous system
1 (4.5%)
Work location
- Hospital Nossa Senhora da Conceição
12 (54.5%)
- Hospital Cristo Redentor
6 (27.3%)
- Hospital Fêmina
2 (9.1 %)
- Conceição Children’s Hospital
1 (4.5%)
- Not identified
1 (4.5%)
N = number of patients.
Results are expressed in absolute numbers (n) and percent (%) and mean ± standard deviation.
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Moraes RB et al.
1,487 employers
105 with cultures
22 with positive
culture
83 with negative
culture
1155 without cultures
or with cultures > 5 days
227 with hospitalization
< 6 months
24 isolated
germs
24 not MRG*
1,382 excluded
0 MRG*
Figure 1 Flowchart allocation of employees with hospitalization.
MRG: multidrug-resistent germs.
valence of germs such as Pseudomonas aeruginosa,
Staphylococcus aureus, Acinetobacter baumannii and Klebsiella pneumoniae among local cultures, stressing local rates
of imipenem resistance at 93% among isolates of Acinetobacter baumannii and 37% positivity for plasmid resistance for Klebsiella pneumoniae carbapenemase (KPC) in the genomic regions blaKPC-1 until blaKPC-7.14,15
Two microorganisms were isolated from urine culture and abdominal fluid samples. Of the pathogens isolated, 14 (58.3%) were considered infectious and 10 (41.7%)
colonizing. Among the admissions analyzed, 3 (13.6%) refer to ICU stays and 1 (4.5%) progressed to death. The only
healthcare worker admitted to ICU and who progressed
to death was diagnosed with Acquired Immunodeficiency
Syndrome and Cryptococcus neoformans isolated in CSF. Despite immunosuppression and ICU admission, this patient
had no positive cultures for MDR bacteria.
Discussion
This study shows the largest sample described to date
with profiles of colonization and infection in healthcare
workers who required hospitalization. The result of our
study suggests that health professionals, even when exposed to MDR bacteria, show no infections or colonization by such germs.
The current evidence on healthcare-associated infections suggests that the bacteria involved in this new classification have resistance profiles different from those
commonly associated with community-acquired infections, in addition to being associated with higher morbidity and mortality.2,4,12.16,17 Few studies that evaluate healthcare-associated infections address healthcare workers.
Given the occupational exposure, it is important to study
the microbiological profile of workers in the health segment. The few studies conducted in this context are limited to exceptional case reports describing rare events of
direct transmission, with both patient and caretaker affected by the same pathogen.6,7 Other reports have also
associated infections in healthcare workers with certain
scenarios from medical practice such as cardiopulmonary
resuscitation rooms,18, 19 operating rooms20 and intensive care units.21,22 The report of unusual cases tends to
wrongly magnify the fear of MDR infection in healthcare workers. Our sample seems more representative of the
actual scenario: the incidence of infections in healthcare
workers was low and mostly the clinical presentation did
not reveal increased severity, being associated with community-acquired germs.
Importantly, in 83 workers who were hospitalized,
the physician found it necessary to collect samples for
culture, and this was done in the first 5 days after admis-
sion; nevertheless, no bacterial growth was found. This
may have occurred for several reasons such as methodological limitation, technical issues, cultures collected after antibiotics were given, or possibly the absence of patient colonization/infection. We observed that in most
patients hospitalized for infectious reasons, the causative germ was isolated. Some, though presenting active infection, had culture results suggestive of colonization,
but the possible microorganism involved in the infection
was not identified.
The average age of our sample was low (49 years) and
predominantly comprised staff members without multiple comorbidities. The fact that these are individuals economically and socially active, also without relevant comorbidities, explains the low incidence of infections in
this population and the lack of data regarding this topic,
as well as the impossibility of carrying out prospective
trials, either observational or clinical in nature.
Our study has several limitations. First, let us remember that this is a unicentric study. Therefore, we consider
it relevant to the literature that many centers report the
incidence of infections and the profile of antibacterial resistance in infections occurring in healthcare workers.
The retrospective design and the definition of contact
with MDRs derived from occupation and the identification of the work segment of the worker do not allow accurate determination of direct contact between the worker and carriers of MDR bacteria, even though the
commission of hospital infection control in this group
does report high rates of colonization with MDR bacteria in the wards.14 Let us keep in mind that out of 1,487
admissions screened, only 22 had pathogens identified.
As possible explanations, we can mention: a significant
number of admissions due to non-infectious causes (individuals economically and socially active, with few comorbidities), the non-systematic collection of samples
for cultures in the first five days from patients hospitalized with infection, the presence of recurrent hospitalizations, and negative cultures in the first 5 days. In our sample, the population was limited to nursing technicians
and other occupations previously mentioned; doctors
and nurses were not included. The fact that HNSC is a
hospital that treats exclusively patients from the Brazilian Unified Health System (SUS public system) can in
part justify this limitation, since those who can afford
health insurance plans are usually admitted to the private network of hospital care. Likewise, some employees
may have been hospitalized in other public hospitals, without our knowledge. Another possible limitation is due
to the low number of infectious cultures in our sample,
since in many cases, even the blood cultures were characterized as colonizing.
Conclusion
In our sample, composed of employees of a public tertiary
care hospital with high rates of colonization by MDR undergoing clinical hospitalization, we found a low prevalence of both infections and colonization. Although evidence
from the literature suggest that the antibiotic spectrum for
empirical treatment of patients with healthcare-associated
infections should be expanded, our results suggest that healthcare workers should not be included in this new classification when presenting infections. Thus, we suggest that
antibiotic therapy is directed towards pathogens with resistance profiles of community-acquired bacteria, since no employee showed colonization or infection with MDRs. In light
of the limitations of this study, further larger and multicenter studies must be developed to enlighten the issue.
Resumo
Perfil microbiológico de profissionais de saúde com internação hospitalar.
Objetivo: conforme perfil epidemiológico e resistência
antimicrobiana, as infecções costumam ser divididas entre comunitárias e nosocomiais. É crescente o relato de
pacientes sem critérios clássicos para infecções nosocomiais com infecções por germes multirresistentes (GMR).
Há particular preocupação perante qual perfil microbiológico deve ser coberto na presença de infecções em profissionais de saúde. Realizamos este trabalho com intuito de identificar a prevalência de infecção por GMR em
profissionais de saúde expostos a contato laboral com
tais germes.
Métodos: estudo observacional, retrospectivo. Em um
período de 7 anos, foram identificadas internações hospitalares de profissionais de saúde e aferidos resultados
de culturas visando a identificar prevalência de infecção
por GMR.
Resultados: identificamos 1.487 internações de profissionais de saúde. Em 105 internações, foram solicitadas
culturas nos primeiros 5 dias de internação. Em 22 internações, foram identificados 24 germes. Não houve isolamento de GMR.
Conclusão: na amostra, composta por funcionários de
um hospital público de nível terciário que apresentaram
internação hospitalar, nenhum funcionário apresentou
colonização ou infecção por GMR. O resultado sugere que
trabalhadores da área de saúde, ao apresentar infecções,
477
Moraes RB et al.
devem receber antibioticoterapia voltada para patógenos
comunitários. Tendo em vista as limitações deste estudo,
são necessários estudos maiores e multicêntricos para elucidar essa questão.
Palavras-chave: infecção hospitalar; resistência antimicrobiana; infecção comunitária; pessoal da saúde.
References
1. Leanne B, Lautenbach E. Prevention and Treatment of healthcare–acquired
infections. Med Clin North Am. 2008;92: 295-313.
2. American Thoracic Society, Infectious Diseases Society of America. Guidelines
for the management of adults with hospital-acquired, ventilator-associated,
and healthcare-associated pneumonia. Am J Respir Crit Care Med.
2005;171:388-416.
3. Mylotte JM. Nursing Home–Associated Pneumonia. Clin Geriatr Med.
2007;23:553-65.
4. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al.
Healthcare–associated bloodstream infections in adults: a reason to change
the accepted definition of community-acquired infections. Ann Intern Med.
2002;137:791-7
5. Baba H, Iinuma Y, Imaizumi K, Hasegawa Y, Hasegawa T, Ohta M, et al.
Transmission of bacterial infections to healthcare workers during intubation
and respiratory care of patients with severe Infect Control Hosp Epidemiol.
2009;30:1019-21.
6. Whitman TJ, Qasba SS, Timpone JG. Occupational transmission of
acinetobacter baumannii from a United States Service man ounded in Iraq
to a Healthcare Worker. Clin Infect Dis.2008;47:439-43.
7. Lacy MD, Horn K. Nosocomial transmission of invasive group A streptococcus
from patient to healthcare worker. Clin Infect Dis. 2009;49:354-7.
8. Vargas SL, Ponce CA, Gigliotti F, Ulloa AV, Prieto S, Muñoz MP, et al.
Transmission of pneumocystis carinii DNA from a patient with P. carinii
Pneumonia to immunocompetent contact healthcare workers. J Clin
Microbiol. . 2000;38:1536-8.
9. Siegel JD, Rhinehart E, Jackson M, Chiarello L. Management of multidrugresistant organisms in healthcare settings. Am J Infect Control. 2007;35(10
Suppl 2):S165-93.
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Dis. 2006;43(Suppl 2):S43-8.
11. Cohen AL, Calfee D, Fridkin SK, Huang SS, Jernigan JA, Lautenbach E, et
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ST, et al. Healthcare- associated pneumonia (HCAP): a critical appraisal to
improve identification, management, and outcomes --proceedings of the
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HNSC. Available from: intranet HNS:H:\PUBLICO\Setores\ CIH-HNSC.
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R, et al. Healthcare-associated pneumonia requiring hospital admission:
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original article
Investigation of urinary abnormalities and risk factors for kidney disease in the World Kidney Day campaigns in Northeast Brazil
Investigation of urinary abnormalities and risk factors for kidney
disease in the World Kidney Day campaigns in Northeast Brazil
Sônia M.H.A. Araújo1, Maria Zenaide D. Ribeiro2, Rafael S. A. Lima2, Geraldo B. Silva Junior1, Camilla N. Jacinto2, Moises
Francisco da Cruz Neto2, Valdenor N. Feitosa Junior2, Marília M. V. Girão2, Elizabeth F. Daher2*
School of Medicine, Post-Graduation Program in Collective Health, Health Sciences Center, University of Fortaleza. Fortaleza, Ceará, Brazil
1
2
Post-Graduation Program in Medical Sciences, Department of Internal Medicine, School of Medicine, Federal University of Ceará. Fortaleza, Ceará, Brazil
Summary
Article received 8/24/2013
*Correspondence:
Address: Rua Vicente Linhares, 1198
Fortaleza, Ceará – Brazil
[email protected] or
[email protected]
http://dx.doi.org/10.1590/1806-9282.60.05.017
Objective: chronic kidney disease (CKD) is an increasing common problem in
the world due to the exponential growth of diabetes mellitus, hypertension and
other risk factors. The aim of this study is to investigate urinary abnormalities
and risk factors for kidney disease in the general population.
Methods: this study was performed from data collected during the annual World
Kidney Day (WKD) campaigns, in Fortaleza, Ceará, Brazil, between 2009 and
2012. The population sought assistance spontaneously in stands placed in high
people-traffic areas.
Results: among 2,637 individuals interviewed, the mean age was 50.7±15.7 years
and 53% were male. The main risk factors found were sedentarism (60.7%), obesity (22.7%) and smoking (19.8%). Blood pressure (BP) > 140x90 mmHg was
found in 877 (33%). Increased BP was found for the first time in 527 cases (19.9%).
Cardiovascular diseases were reported in 228 (8.6%). Diabetes was related by 343
(13%). Capillary blood glucose > 200 mg/dL was found in 127 (4.8%) and it was
> 200 mg/dL for the first time in 30 (1.13%). Urinalysis was performed in 1,151
people and found proteinuria in 269 (23.3%). Proteinuria was most frequent in
hypertension people (77.3% vs. 55.8%, p=0.0001), diabetes mellitus (22.7% vs. 15.2%,
p=0.005) and elderly (42.1% vs. 30.7%, p=0.0007).
Conclusion: risk factors for CKD are frequent in the general population. Many
individuals had hypertension and diabetes and did not know this. It is important to regularly perform actions like WKD in order to early detect potential
candidates for CKD.
Keywords: world kidney day, urinary abnormalities, chronic kidney disease, hypertension, diabetes mellitus.
Introduction
Chronic kidney disease (CKD) is an increasing common
problem in the world. CKD is now a global public health
problem due to the exponential growth of diabetes mellitus, hypertension and other risk factors.1 By 2030, the
number of people undergoing kidney replacement therapy in the United States is expected to increase to more
than 2 million.1
Early detection of kidney disease offers the potential
to improve outcomes by allowing for more time to intervene when most patients are still asymptomatic.2 Abnor-
mal results identified during screening tests are not considered diagnostic but rather indicative of increased risk.
There are few studies investigating renal dysfunction in
the general population in Brazil. In a previous study conducted in the State of Minas Gerais, the prevalence of elevated creatinine was higher in the elderly.3 In another
study investigating the prevalence of CKD (stages 3, 4
and 5) in adults was 9.6%.4
End-stage renal disease (ESRD) has reached epidemic proportion with more than 400,000 affected individu-
479
Araújo SMHA et al.
als in the United States and over one million worldwide.5
This staggering number represents only the tip of the iceberg, as the incidence of chronic kidney disease (CKD) is
at least 30-fold higher than that of ESRD.6
The CARE project identified 56% of 348 individuals
as at risk of diabetes, hypertension, and/or kidney disease and supported the feasibility of a regional targeted
kidney disease screening action to identify individuals at
risk.7
The aim of this study is to investigate urinary abnormalities and risk factors for kidney disease in the general population.
dents and professors of the Federal University of Ceará.
Patients identified as having hypertension and/or diabetes were referred to the outpatients’ clinics of the Walter
Cantídio University Hospital.
Statistical analysis was performed using Epi-Info, version 6.04b. The results were expressed by means ± standard deviation or relative frequencies. Comparison of parameters for two groups was done by means of Student’s
t test and Fisher’s exact test. A comparison between patients with and without proteinuria was done. Descriptive values below 5% (p < 0.05) were considered statistically significant.
Methods
This study was performed from data collected during the
annual World Kidney Day campaigns in Fortaleza, Ceará,
Brazil, on 11th March 2009, 10th March 2010, 10th March
2011 and 8th March 2012. During the events, stands were
placed in high people-traffic areas in which the population sought assistance spontaneously. The protocol of
this study was approved by the ethics committee of the
Federal University of Ceará, Brazil. A signed consent was
obtained before filling out the forms.
The following data were collected: age, gender, weight,
height and cardiovascular risk factors (smoking, physical inactivity, obesity and family history). Body mass index (BMI) was calculated using weight and height, and
obesity was considered as BMI ≥30kg/m2. Physical inactivity was considered when the individual reported expending less than 10% of their daily energy in the performance of moderate- and high-intensity activities.8
The following services were offered: guidelines for a
healthy lifestyle, blood pressure and capillary blood glucose (with the equipment One touch ultra – Johnson &
Johnson) measurement and urinalysis (dipstick Neocheck
– Neomedica). Urinalysis was offered for each interviewed
individual and it was performed for those who accepted
to collect a urine sample.
Blood pressure was measured according to standard
methods with free-mercury aneroid equipment (Welch
Allyn – Tycos®). Patients were calmly seated in a chair for
at least 5 minutes before their blood pressure was measured, their feet were placed on the floor and the arm
where blood pressure would be measured was at the height
of the heart. Patients had not drunk any coffee and had
not smoked or made physical exercise 30 minutes before
blood pressure was measured. A cuff of appropriate size
was used. Two blood pressure measurements were done
in the right arm, with 5 minutes interval, and the average
was calculated.9 The tests were performed by medical stu-
Results
A total of 2,637 individuals were interviewed. The mean
age was 50.7 ± 15.7 years and 53% were male. The main
cardiovascular risk factors found were sedentary lifestyle
(60.7%), obesity (22.7%) and smoking (19.8%). Previous
diagnosis of hypertension was related by 906 (34.3%) individuals. Blood pressure higher than 140/90 mmHg was
found in 877 (33%) participants. First finding of increased
blood pressure was found in 527 (19.9%). Cardiovascular
diseases were reported in 228 (8.6%). Diabetes was related by 343 (13%) individuals. Capillary blood glucose higher than 200 mg/dL was found in 127 (4.8%) and it was
higher than 200 mg/dL for the first time in 30 cases
(1.13%). The majority of the interviewed (38.6%) presented capillary blood glucose between 100 and 126mg/dL.
Urinalysis was performed in 1,151 patients and found
proteinuria in 269 cases (23.3%). Proteinuria was most frequent in patients with hypertension (77.3% vs. 55.8%,
p = 0.0001), diabetes mellitus (22.7% vs. 15.2%, p = 0.005)
and elderly individuals (42.1% vs. 30.7%, p=0.0007).
Discussion
There are few studies investigating the prevalence of CKD
in the general population. Our study tried to identify risk
factors for renal dysfunction in the general population
in a metropolitan area in Brazil, mainly hypertension,
diabetes mellitus and proteinuria. The National Kidney Foundation’s Kidney Early Evaluation Program (NKF KEEP)
identifies individuals at increased CKD risk by using inclusion and exclusion criteria.10 People are included if
they have at least one of the following criteria: hypertension, diabetes and family history of hypertension, diabetes and chronic kidney disease. Individuals undergoing
renal replacement therapy or kidney transplantation were
excluded. The overall CKD prevalence found was 29% and
only 7% self-reported CKD, demonstrating low CKD awareness in general population.10
In the present study with 2,637 individuals, the mean
age was 51 years and 53% were male. NKF KEEP included 61,675 participants with 54 years and 68% were female.10 KEEP Japan included 1,065 participants with 60
years old and 53% were female.11 In KEEP Mexico, 1,519
individuals participated and more than 70% were female.12
High blood pressure was found in 33% of measurements and first finding of increased blood pressure was
found in 20% of subjects in our study, which means that
an important proportion of patients had hypertension
and did not know it. Among NKF KEEP participants, 66%
have increased blood pressure, 17% have isolated measured hypertension and 53% have self-reported hypertension.10 Hypertension was self-reported in 59%10,11 and in
62% in KEEP Mexico.12
In our cohort, diabetes was related by 13%. Capillary
blood glucose higher than 200 mg/dL was found in 5%
and it was higher than 200 mg/dL for the first time in 1%,
which can be considered as diagnosis of diabetes. NKF
KEEP data found that 30% of participants have diabetes,
self-reported (25%) or based on glucose testing alone
(5%)10. Fifty percent of NKF KEEP participants who selfreported diabetes have a high measured glucose level. In
KEEP Japan, 27% self-reported diabetes. Glycemic control was higher than 139 mg/dL for 35% of diabetic participants. High blood glucose was newly found in 21 participants.11
Among all participants, 20.8% in KEEP Japan and
21.2% in NKF KEEP self-reported one or more cardiovascular diseases.10,11 In the present study, these conditions
were reported in 9% of individuals.
Urine protein, determined by the dipstick method,
was positive for 7.2% in KEEP Japan.11 Abreu et al.13 found
26% of hematuria e 5% of proteinuria among 200 elderly
subjects in São Paulo, Brazil. Different from others reports, in the present study, urinalysis was performed in
1,151 individuals and found a high level of proteinuria
(23.3%).
This study has some limitations. The findings may
not be generalizable to the total Brazilian population as
the study includes only self-referred population. We could
not estimate glomerular rate filtration because there was
no measurement of serum creatinine. A single measurement of blood pressure in health campaigns does not allow diagnosing hypertension nor preclude the possibility of white-coat effect.
Lack of health insurance is an independent risk factor for early death and ESRD in individuals with high
risk of kidney disease.14 The goals of early CKD detection
are to prevent CKD progression and associated compli-
cations, thus improving patient outcomes. Campaigns
are important to warn people who may be at risk of developing hypertension and for those who already have
hypertension and had not yet been diagnosed.
In summary, risk factors for CKD are frequent in the
general population. Many individuals had hypertension
and diabetes and did not know it. It is important to regularly perform actions like WKD in order to early detect
potential candidates for CKD. Campaigns like World Kidney Day have a good cost-effectiveness ratio because in
the absence of more elaborated studies to evaluate the
prevalence of CKD they act as an alert to the population
of the risk of hypertension and diabetes, mainly in people with family history, overweight, obesity, sedentarism
and other risk factors for renocardiovascular diseases.
Studies like this are important to early detect risk factors
for renal function loss and to adopt measures to slow the
progression of kidney disease. These measures can impact public health since fewer patients would need renal
replacement therapy if kidney disease is detected in early stages.
Table 1 Epidemiological characteristics and risk factors
for chronic kidney disease in 2,637 individuals in Northeast
Brazil
N
%
18-30
312
11.8
31-45
674
25.5
Age, years
46-60
891
33.7
61-75
618
23.4
>75
142
5.3
Male
1235
47
Female
1402
53
Smoking
523
19.8
Physical inactivity
1601
60.7
Obesity
599
22.7
Cardiovascular diseases
228
8.6
Proteinuria
269
23.3
Gender
Risk factors
Table 2 Urinary findings in 1,151 in participants
Northeast of Brazil
N
%
Proteinuria
269
23.3
Leukocyturia
144
12.5
Hematuria
38
3.3
481
Araújo SMHA et al.
Table 3 Comparison of individuals with and without proteinuria among 1,151 participants in Northeast Brazil
With proteinuria
Age, years
Without proteinuria
(n = 269)
(n = 882)
P
54.3±15.8
51.4±14.5
0.005
Gender
Male (%)
117 (43.5)
393 (44.6)
Female (%)
152 (56.5)
489 (55.4)
0.77
64 (23.7)
204 (23.1)
0.86
Obesity (%)
80 (29.7)
234 (26.5)
0.30
Sedentarism (%)
172 (63.9)
556 (63)
0.82
Diabetes mellitus (%)
56 (20.8)
120 (13.6)
0.005
CBG > 200 mg/dL (%)
5 (1.8)
14 (1.5)
0.78
Hypertension (%)
155 (57.6)
318 (36)
0.0001
BP > 140x90 mmHg
53 (19.7)
175 (19.8)
1.0
SBP (mmHg)
138±22
129±19
0.0001
DBP (mmHg)
85±12
82±11
0.0001
Smoking (%)
Cardiovascular diseases (%)
33 (12.2)
34 (3.8)
0.0001
Renal diseases family history (%)
44 (16.3)
71 (8.0)
0.0002
BMI (kg/m2)
28.1±4.8
27.5±4.5
0.05
CBG = Capillary blood glucose, BP = blood pressure, SBP = systolic blood pressure, DBP = diastolic blood pressure, BMI = body mass index. Values expressed as mean ± SD. Significant P < 0.05.
Resumo
Investigação de alterações urinárias e fatores de risco para
doença renal nas campanhas do Dia Mundial do Rim no
nordeste do Brasil.
Objetivo: a doença renal crônica (DRC) é um problema
crescente no mundo em razão do crescimento exponencial do diabetes mellitus, da hipertensão e de outros fatores
de risco. O objetivo deste estudo é investigar alterações
urinárias e fatores de risco para doença renal na população geral.
Métodos: este estudo foi realizado a partir de dados coletados durante as campanhas anuais do Dia Mundial do
Rim, em Fortaleza, Ceará, Brasil, entre 2009 e 2012. A população buscou atendimento espontaneamente nos stands
montados em locais de alto tráfego de pessoas.
Resultados: entre 2.637 indivíduos entrevistados, a média de idade foi de 50,7±15,7 anos, sendo 53% do gênero
masculino. Os principais fatores de risco encontrados foram sedentarismo (60,7%), obesidade (22,7%) e tabagismo (19,8%). Pressão arterial (PA) > 140x90 mmHg foi encontrada em 877 casos (33%). Aumento da PA foi
encontrado pela primeira vez em 527 casos (19,9%). Doenças cardiovasculares foram relatadas por 228 indivíduos
(8,6%). Diabetes foi relatado por 343 indivíduos (13%).
Glicemia capilar > 200 mg/dL foi encontrada em 127 ca-
sos (4,8%) e > 200 mg/dL pela primeira vez em 30 (1,13%).
O exame de urina foi realizado por 1.151 pessoas, sendo
encontrada proteinúria em 269 casos (23,3%). Proteinúria foi mais frequente em pessoas com hipertensão (77,3%
vs. 55,8%, p = 0,0001), diabetes mellitus (22,7% vs. 15,2%,
p = 0,005) e em idosos (42,1% vs. 30,7%, p = 0,0007).
Conclusão: fatores de risco para DRC são frequentes na
população geral. Muitos indivíduos tinham hipertensão
e diabetes e não sabiam disso. É importante a realização
de ações como o Dia Mundial do Rim com o objetivo de
detectar precocemente potenciais candidatos à DRC.
Palavras-chave: Dia Mundial do Rim; alterações urinárias; doença renal crônica; hipertensão; diabetes mellitus.
References
1. Gilbertson DT, Liu J, Xue JL, Louis TA, Solid CA, Ebben JP, et al. Projecting
the number of patients with end-stage renal disease in the United States to
the year 2015. J Am Soc Nephrol. 2005;16:3736-41.
2. Vassalotti JA, Li S, Chen SC, Collins AJ. Screening populations at increased
risk of CKD: the Kidney Early Evaluation Program (KEEP) and the public
health problem. Am J Kidney Dis. 2009;53(3 Suppl 3):S107-S14.
3. Passos VMA, Barreto SM, Lima-Costa MFF, The Bambuí Health and Ageing
Study (BHAS) Group. Detection of renal dysfunction based on serum
creatinine levels in a Brazilian community. The Bambuí Health and Ageing
Study. Braz J Med Biol Res. 2003;36:393-401.
4. Bastos RMR, Bastos MG, Ribeiro LC, Bastos RV, Teixeira MTB. Prevalência
da doença renal crônica nos estágios 3, 4 e 5 em adultos. Rev Assoc Med
Bras. 2009;55:40-4.
5. Satko SG, Freedman BI, Moossavi S. Genetic factors in end-stage renal
disease. Kidney Int Suppl. 2005;(94):S46-S9.
6. Jones CA, McQuillan GM, Kusek JW, Eberhardt MS, Herman WH, Coresh
J, et al. Serum creatinine levels in the US population: third National Health
and Nutrition Examination Survey. Am J Kidney Dis. 1998;32:992-9.
7. Brown WW, Collins A, Chen SC, King K, Molony D, Gannon MR, et al.
Identification of persons at high risk for kidney disease via targeted screening:
The NKF Kidney Early Evaluation Program. Kidney Int Suppl.
2003;(83):S50-S5.
8. Bernstein MS, Morabia A, Sloutskis D. Definition and prevalence of
sedentarims in an urban population. Am J Public Health. 1999;89:862-7.
9. Chobanian A, Bakris G, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al.
Seventh report of the Joint National Committee on Prevention, Detection,
Evaluation and Treatment of High Blood Pressure. Hypertension.
2003;42:1206-52.
10. National Kidney Foundation: KEEP Kidney Early Evaluation Program
Annual Data Report 2006. Am J Kidney Dis. 2007;49(1 Suppl 1):S1-S160.
11. Takahashi S, Okada K, Yanai M. The Kidney Early Evaluation Program
(KEEP) of Japan: results from the initial screening period. Kidney Int Suppl.
2010;(116):S17-S23.
12. Obrador GT, García-García G, Villa AR, Rubilar X, Olvera N, Ferreira E, et
al. Prevalence of chronic kidney disease in the Kidney Early Evaluation
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483
Original Article
Munhoz LO et al.
How to evaluate quality of life in overweight and obese women
during climacterium?
Livia Oliveira Munhoz1*, Isabel Cristina Esposito Sorpreso2, Maria Cristina Caceres Nogueira3, Ricardo dos Santos
Simões4, José Maria Soares Junior5, Edmund Chada Baracat6
Resident in Obstetrics and Gynecology, Faculty of Medicine, University of São Paulo, Brazil.
1
2
Adjunct Professor in Gynecology, Department of Obstetrics and Gynecology, Faculty of Medicine, University of São Paulo, Brazil.
3
Collaborating Physician in the Division of Gynecology, Department of Obstetrics and Gynecology, Faculty of Medicine, University of São Paulo, Brazil.
Assistant Physician Doctorate student in Obstetrics and Gynecology at the Faculty of Medicine, University of São Paulo, Brazil.
4
5
Associate Professor in the Division of Gynecology, Department of Obstetrics and Gynecology, Faculty of Medicine, University of São Paulo, Brazil.
6
Full Professor in the Division of Gynecology, Department of Obstetrics and Gynecology, Faculty of Medicine, University of São Paulo, Brazil.
Summary
Division of Gynecology, Department of
Obstetrics and Gynecology, School of
Medicine at University of São Paulo
Approved for publication: 7/23/2014
*Correspondence: Instituto Central do Hospital das
Clínicas da Faculdade de Medicina da
Universidade de São Paulo,
Address: Av. Dr. Enéas de Carvalho Aguiar,
255, 10o andar
Cerqueira César,
[email protected]
Objective: identifying the instruments used to measure quality of life during menopausal transition and post-menopause in women with obesity or overweight.
Methods: a systematic search using the Embase, Pubmed and Cochrane databases, and the following key-words: menopause/climacteric, quality of life, overweight/obesity. Nineteen papers that fulfilled the including criteria were found.
Results: eighteen studies using generic health questionnaires (global quality of
life) were identified, six of them were specific for menopause and one specific for
obesity. Eleven studies used generic questionnaires, while only eight questionnaires were specific for menopause.
Conclusion: there was no consensus in the literature about the use of quality
of life questionnaires in women with overweight and obesity in climacterium,
which makes de comparison and reproducibility of the results difficult. This is
an alert about the need for standardization to better evaluate this specific population.
http://dx.doi.org/10.1590/1806-9282.60.05.018
Keywords: menopause, climacteric, overweight, obesity, quality of life.
Introduction
Obesity is a multifactorial disease, epidemic in nature,
which according to the World Health Organization affects over 300 million adults worldwide. Overweight individuals correspond to about one billion adults.1 The
body mass index (BMI) of women seems to reach its
highest values between

50 and 59 years, a period that often coincides with menopause.2
This period is characterized by body aging linked to
progressive hypoestrogenism, which not only triggers
health implications, but is also associated with changes
in women’s lives. Characteristic symptoms may be observed, including vasomotor, psychological, urogenital, sleep
disturbances and sexual dysfunction, as well as difficulties in emotional and social sphere.3-6 The quality of life
in postmenopausal women is a major subject, because its
results can help define therapeutic approaches and promote healthier aging for females, with improved quality
of life.4,5,7
Research shows associations among obesity, menopausal symptoms and worse quality of life.5,8-17 To conduct this evaluation, various types of questionnaires are
used, both generic - analyzing overall quality of life for
any population - and specific questionnaires to analyze
the quality of life in the transition to menopause and
postmenopause.18-21
The objective of this work is to identify the instruments used to measure the quality of life of overweight
and obese women in climacteric age (during the transi-
tion to menopause and post-menopause), through a systematic review of the literature.
Methods
A systematic search was performed using the Embase,
Pubmed and Cochrane databases, and the following key-words: menopause/climacteric, quality of life, overweight/
obesity. Full articles and editorials in English, Portuguese and Spanish were selected. Inclusion criteria were: full
articles that used at least one questionnaire to assess
quality of life or questionnaire related to climacteric
symptoms, being at least part of the sample comprised
of patients with overweight, obesity or metabolic syndrome who were also in transition to menopause and
post-menopause. Exclusion criteria were: case reports
and systematic reviews. Using these criteria were selected twenty-two articles after reading the title and abs-
tract. After reading the full articles, three were excluded
for the following reasons: the first examined only psychological well-being, the second used questionnaires of
quality of life specific to women with breast cancer, and
the third used specific questionnaires for urinary incontinence and sexual function. In the end, 19 articles were
selected for this systematic review.
Results
Nineteen articles were found in the systematic literature
search. The characteristics of both the articles and questionnaires used are summarized in Table 1. The studies
were published between 1999 and 2013, and ten of these
were dated 2009 or later. The different populations ranged from 40 to 70 years of age, n ranged from 30 to 161.393
women, with the majority (13) of research having n of
200-1,194.
Table 1 Summary of articles that used questionnaires to assess quality of life in overweight or obese women in transition to
menopause and post-menopause, identifying the year of publication, the instrument used, age range and/or mean population
and number of participants
Year
2013
Author
Ashok P et al.22
Instruments
Age (mean)
World Health Organization five-item well-being index (WHO- 40-60
n
60
2012
2011
Gallon CW et al.33
Imayama I et al.23
5)
Menopause Rating Scale (MRS)
40-65 (52.8)
SF-36; Brief Symptom Inventory-18; Perceived Stress Scale; 50-75 (58)
200
439
2011
2010
Heidelberg DA et al.24
Lynch CP et al.25
Social Support Survey
SF-12
Items taken from instruments used in the WHI trial to assess
35-74
50-79
983
161,393
emotional aspects of quality of life; SF-36 to evaluate physical
2010
2010
Alonso AMF et al.9
Riesco E et al.26
aspects of quality of life
Kupperman Index
SF-36
(49.9)
Pre-menopausal women (49)
574
30
2009
2009
2009
2009
2008
González FG et al.27
Castelo-Branco C et al.34
Llaneza P et al.35
Messier V et al.28
Karelis AD et al.29
EuroQol 5-D; Rosenberg Self-Esteem Scale
Cervantes Scale
Cervantes Scale
Medical Outcomes Study General Health Survey (MOS)
Medical Outcomes Study General Health Survey (MOS);
Post-menopausal women (52)
(60.53)
45-64 (54.38)
50-65
46-70
46-70
106
284
496
136
137
Perceived Stress Scale; Self- Esteem Scale; Body-Esteem
Scale; Scale of perceived risk for developing heart disease
2008
2007
2007
Yankura DJ30
Llaneza P et al.36
Lemoine S et al.31
or diabetes
SF-36
Cervantes Scale
SF-36; Three-Factor Eating Questionnaire
52-62
580
50-64
250
Pre-menopausal women 30-45(39) 40
2007
2007
2006
1999
Daley A et al.37
Chedraui P et al.38
Mirzaiinjmabadi K et al.39
Raikkonen K et al.32
Women’s Health Questionnaire (WHQ)
MENQOL
Greene Scale
SF-36; Beck Depression Inventory; Spielberg Trait Anger/
Post-menopausal women 49-64 (56)
46-55 (50.5)
1,194
40-70 (55.9)
325
45-60
883
45-53
345
Anxiety Questionnaire; Scale for distress; Interpersonal
Support Evaluation List (ISEL)
485
Munhoz LO et al.
Twenty-four questionnaires were identified in nineteen articles (Table 2). The instruments found were divided into generic, assessing overall quality of life in any
population; specific, for quality of life in women during
transition to menopause and post-menopause; and restricted, for psychosocial aspects of quality of life.
Table 2 List of assessment tools for quality of life used
in overweight and obese women in transition to
menopause and post-menopause, identifying the type of
instrument, frequency of use, and year of use
Instrument
World Health Organization
Type
Frequency
Year
five-item well-being index
EPS
1
2013
EM
1
2012
SF-36
G
6
Brief Symptom Inventory-18
Social Support Survey
SF-12
Perceived Stress Scale
Items taken from
EPS
EPS
G
EPS
1
1
1
2
2008, 2007, 1999
2011
2011
2011
2008, 2011
(WHO-5)
Menopause Rating Scale
(MRS)
2011, 2010, 2010,
instruments used in the
EPS
1
2010
WHI trial
Kupperman Index
EuroQol 5-D
Rosenberg Global
EM
G
1
1
2010
2009
Self-Esteem Scale
Cervantes Scale
Medical Outcomes Study
EPS
1
2009
EM
3
2009, 2009, 2007
General Health Survey
G
2
2009, 2008
(MOS)
Self- Esteem Scale
Body-Esteem Scale
Scale of perceived risk for
EPS
EPS
1
1
2008
2008
developing heart disease or
EPS
1
2008
EPS
1
2007
EM
1
2007
EM
EM
EPS
1
1
1
2007
2006
1999
EPS
1
1999
EPS
1
1999
EPS
1
1999
diabetes
Three-Factor Eating
Questionnaire
Women’s Health
Questionnaire (WHQ)
MENQOL
Greene Scale
Beck Depression Inventory
Spielberg Trait Anger/
Anxiety Questionnaire
Scale for Distress
Interpersonal Support
Evaluation List (ISEL)
G: generic quality of life instrument; EM: specific instrument for quality of life in the transition
to menopause and post-menopause; EPS: specific instrument for psychosocial aspects of quality of life.
Four different instruments were identified to assess overall
quality of life. For specific analysis of quality of life related
to the climacteric period, six different questionnaires were
used. Most instruments found (fourteen) aimed to quantify the quality of life related to psychosocial aspects.
The SF-36 was observed more frequently, being used
in six articles published from 1999 to 2011. The second
most frequently found was the Cervantes Scale, seen in
three articles, two published by a single group of researchers (Lhaneza et al.35,36). The Medical Outcome Study
General Health Survey (MOS) was used in two articles,
and the other questionnaires in one study only.
Six studies used more than one instrument to measure quality of life. Eight studies used specific questionnaires for menopause, while 11 used generic questionnaires, combined or not with instruments for psychosocial
analysis.
Discussion
The nineteen studies obtained used twenty-four different
scales. Eleven used generic questionnaires,22-32 while eight
employed specific instruments to assess quality of life in women before and after menopause.9,33-39 A single article made
reference to a specific questionnaire related to obesity.31
The SF-36 and Medical Outcomes Study General
Health Survey (MOS) questionnaires, which are derived
from the same study, were the most prevalent generic
tools, being found in eight articles.23,25,26,28-32 The SF-36
was the most widely adopted, being found in six articles,23,25,26,30-32 which is consistent with the literature, since it is the most widely used generic instrument documented in over four hundred publications.40,41 However,
none of these questionnaires takes into consideration important aspects such as menopausal symptoms or specific psychosocial conditions regarding this time of life,
which hinders the assessment of quality of life in this population. The social psychological aspect was measured
by fourteen different scales covering aspects of emotional health and the social structure in which the individual lives, which affect the quality of life. Six articles used
generic instruments combined with psychosocial questionnaires, showing that the use of generic instruments
may fail to take into account important aspects of quality of life in the period close to menopause.23,25,27,29,31,32
Ashok et al.22 used the World Health Organization five-item well-being index (WHO-5) well-being questionnaire, which assesses psychological and not physical dimensions related to menopause.22 Lynch et al.25 used the
SF-36 together with a questionnaire to determine psychosocial quality of life created from instruments used in the
Women’s Health Initiative (WHI) trial.25 Therefore, the
article used its own instrument, unlike those classically
found in the literature, which demonstrates the lack of
standardization in the literature.
Eight of the nineteen studies used specific questionnaires for menopause.9,33-39 The Cervantes Scale was the
most prevalent, found in three of them.34-36 The instrument
was developed in Spanish, mainly for use in this population, and translated into Portuguese, despite being validated in a limited number of countries.42 In these three studies, two were conducted by the same author (Llaneza et
al.9, making it difficult to generalize the results.35,36 Alonso et al.39 used the Kupperman Index, according to the data
found in the literature about its widespread use, even with
criticism for not addressing urogenital, social and other
symptoms related to sexuality.9,43-45 Mirzaiinjmabadi et al.39
used the Greene Scale, a list of 21 items including psychological, vasomotor and somatic symptoms, which was not
exactly designed as an instrument of quality of life.21,39 The
other specific questionnaires were: Menopause Rating Scale (MRS), Women’s Health Questionnaire (WHQ) and Menopause-Specific Quality of Life Questionnaire (MENQOL), which have already been validated and are the main
scales currently used in studies on women in transition to
menopause and post-menopause.33,37,38,43,46,47 In Brazil, only
WHQ, MENQOL and Cervantes Scale were validated; Greene Scale has been used for many years, and MRS is being
used even without validation.
Lemoine et al.31 was the only author who used a specific questionnaire for obesity, the Three-Factor Eating
Questionnaire, which is related to psychological well-being. Thus, it is important to assess the need to use specific questionnaires for obesity since the population in question is also subject to the effects of obesity as a
comorbidity on quality of life.31
There is no consensus as to the best type of instrument to be used to assess quality of life. Fayers et al.41 believes that both generic and specific measures have advantages and disadvantages. He recommends the use of
generic and specific instruments wherever possible, in
combination, to give strength to both approaches.41 On
the other hand, many researchers prefer to use specific
questionnaires to assess a certain condition. Chedraui et
al.38 states that specific instruments are required in each
condition, and menopause, or climacterium, is not an exception.38 Utian16 believes that in order to evaluate the
quality of life of women in transition to menopause and
post-menopause, somatic symptoms such as hot flashes,
night sweats, genital atrophy and urinary incontinence,
and psychological symptoms such as mood swings and
life circumstances, should be included; i.e., occupational,
sexual, emotional and health-related factors.16 Schneider
et al.21 argues that the instrument must have certain attributes or properties of measures suitable for a particular
purpose. Specific questionnaires are more sensitive to
change and make sense for both the physician and patient, since the items included report highly relevant domains to that particular population.21
The varied use of questionnaires can be justified by
the researcher’s choice for the most widely used instruments such as the SF-36 and also the preference of certain authors to use surveys created in the language and
targeted to the cultural context of the study population.48 The predilection for generic tools found in the articles used in this review fails to analyze important characteristics of the study population, given the peculiarities
of both the period of transition to menopause and post-menopause and obesity. Therefore, assessment of the quality of life of these women was hindered.
Conclusion
The most widely used instrument for assessing quality of
life in obese women in transition to menopause and post-menopause was the generic SF-36 questionnaire. The Cervantes Scale was the specific instrument most used. There was no consensus regarding the use of the instruments,
which is an obstacle for comparison and reproducibility
of results. The current study is a warning to researchers
that there is a need for a standard instrument to assess
this growing population.
Resumo
Como aferir qualidade de vida de mulheres com sobrepeso e obesidade no climatério?
Objetivo: identificar os instrumentos utilizados para aferir a qualidade de vida de mulheres com sobrepeso e obesidade no climatério (transição para menopausa e pós-menopausa).
Métodos: busca sistemática nas bases de dados Embase,
Pubmed e Cochrane com os descritores: menopause/climacteric, quality of life, overweight/obesity. Foram incluídos 19
artigos que preencheram os critérios de inclusão.
Resultados: foram identificados 18 questionários genéricos (qualidade de vida global), 6 específicos para menopausa e 1 específico para obesidade. Onze estudos utilizaram instrumentos genéricos, enquanto 8 utilizaram
específicos para menopausa.
487
Munhoz LO et al.
Conclusão: não houve consenso na literatura quanto ao
uso de instrumentos de qualidade de vida em mulheres
com sobrepeso e obesidade no climatério, o que dificulta a comparação e a reprodutibilidade dos resultados. Este
é um alerta quanto à necessidade de padronização para
melhor avaliar essa população específica.
Palavras-chave: menopausa; climatério; sobrepeso; obesidade; qualidade de vida.
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489
Review article
Coimbra S et al.
Susana Coimbra1,2*, Rafael Neves3, Margarida Lima4, Luís Belo1,3, Alice Santos-Silva1,3
Institute of Molecular and Cellular Biology (IBMC), University of Porto, Porto, Portugal.
1
2
CESPU, Institute for Research and Advanced Training in Health Sciences and Technologies, Gandra-PRD, Portugal.
3
Department of Biological Sciences, Biochemistry Laboratory, Faculty of Pharmacy, University of Porto, Porto, Portugal.
Santo António General Hospital, Centro Hospitalar of Porto, Porto, Portugal.
4
Summary
Study conducted at the University of Porto,
Porto, Portugal
*Correspondence:
Instituto de Biologia Molecular e Celular
(IBMC), Universidade do Porto
Address: Rua do Campo Alegre, 823
Postal Code: 4150
Porto – Portugal
Phone: 351 962677495
[email protected]
http://dx.doi.org/10.1590/1806-9282.60.05.019
Waldenström’s macroglobulinemia (WM) is a lymphoproliferative disease of B
lymphocytes, characterized by a lymphoplasmocytic lymphoma in the bone marrow and by IgM monoclonal hypergammaglobulinemia. It was first described in
1944 by Jan Gösta Waldenström, reporting two patients with oronasal bleeding,
lymphadenopathy, anemia, thrombocytopenia, high erythrocyte sedimentation
rate and serum viscosity, normal radiography and bone marrow infiltrated by
lymphoid cells.
The WM is a rare disease with a typically indolent clinical course, affecting mainly
individuals aged between 63 and 68 years. Most patients have clinical signs and
symptoms related to hyperviscosity resulting from IgM monoclonal gammopathy, and/or cytopenias resulting from bone marrow infiltration by lymphoma.
The differential diagnosis with other lymphomas is essential for the assessment
of prognosis and therapeutic approach.
Treatment of patients with asymptomatic WM does not improve the quality of
life of patients, or increase their survival, being recommended, therefore, their
follow-up. For the treatment of symptomatic patients, alkylating agents, purine analogs and anti-CD20 monoclonal antibodies are used. However, the disease is incurable and the response to therapy is not always favorable. Recent studies have shown promising results with bortezomib, an inhibitor of proteasomes,
and some patients respond to thalidomide. In patients with relapse or refractory to therapy, autologous transplantation may be indicated.
The aim of this paper is to describe in detail the current knowledge on the pathophysiology of WM, main clinical manifestations, diagnosis, prognosis and
treatment.
Keywords: Waldenström’s macroglobulinemia, hypergammaglobulinemia, IgM,
lymphocytes B. prognosis.
Introduction
Waldenström’s macroglobulinemia (WM), described in
1944 by Jan Gösta Waldenström, is a lymphoplasmacytic
lymphoma (LPL) characterized by IgM monoclonal hypergammaglobulinemia and bone marrow infiltration.1
LPLs are rare and indolent cancers of mature B-lymphocytes, which predominantly involve the bone marrow
and, less commonly, the spleen, lymph nodes, peripheral
blood and other organs.1
Epidemiology
WM has an estimated incidence of 3 cases/million/year,
accounting for about 2% of all hematological cancers.2
There is a higher incidence in individuals aged between
63 and 68 years.3 Approximately 60% of patients are men,
and it is more common in caucasian indivuals.3 The average survival is 5 years,3 however, approximately 10% of
patients survive up to 15 years.4 As the disease is mainly
diagnosed in old age, about 50% of patients die due to
comorbidities not related directly to WM.3
Etiology
Its etiology is unknown, but several studies suggest a possible causal relationship with autoimmune diseases, exposure to environmental factors and chronic antigenic
stimulation, such as infection with the hepatitis C virus
(HCV). Despite the high incidence of HCV infection in
these patients, a statistically significant association
between HCV infection and WM has not been found.5
In relation to familial predisposition, an association
is estimated in 20% of cases.6,7 In first degree family relations there is a high risk of developing lymphoproliferative diseases, which is twenty times higher for WM/LPL.8
Pathophysiology
It is believed that WM originates in memory B-lymphocytes.9,10 These lymphocytes descend from B-lymphocytes
that proliferate in the germinal centers of lymph nodes
(post-germinal center B-lymphocytes), accumulating all
the genetic changes that occur in these centers. Thus, in
most cases, the neoplastic B cells present somatic hypermutation in the genes coding the hypervariable regions of
the immunoglobulin heavy chains (VH genes).11,12 However, in some cases, the neoplastic B-cells are derived from
B-lymphocytes which have undergone somatic mutation
outside of germinal centers.13 In other cases, there is no
evidence of somatic mutations in the VH genes, which may
indicate that they are derived from pre-germinal center B-lymphocytes, such as “virgin” B-lymphocytes.12
In relation to the mechanisms involved in the pathophysiology of WM, the blocking of immunoglobulin isotype switching and the role of cytokines is noteworthy.
Most malignant cells in WM express surface IgM and
IgD, suggesting an intrinsic incapacity to switch isotypes.13 This “block” may be related to the absence/dysfunction of the activation-induced cytidine deaminase (AID)
enzyme, which is involved in somatic hypermutation and
the immunoglobulin isotype switching process.11,13
Although isotype switching is rarely seen in WM, according to some studies it is possible that it occurs ex vivo
and in vivo. Kriangkum et al.11 demonstrated that AID
may be induced ex vivo, by stimulation with CD40L and
interleukin-4 (IL-4). Another study showed the possibility of isotype switching occurring in vivo.14
Mast cells and various cytokines play an important
role in the development of the disease.15 Cytokines may
be important for angiogenesis, increased bone resorption,
proliferation, survival of malignant cells, and secretion
of monoclonal IgM.
In WM, malignant B-lymphocytes express the receptor CD27,13 which can be found in the membrane of memory B-lymphocytes and in soluble form (sCD27) in high
concentrations in the serum.15 sCD27 activates bone marrow mast cells by binding to CD70. Activated mast cells
secrete growth and survival factors for B-lymphocytes
such as CD40L and APRIL (proliferation-inducing ligand),15 which may contribute to lymphoplasmocytoid
differentiation of malignant cells in the bone marrow.
Clinical symptoms
The clinical presentation of WM varies. Most of the patients present clinical signs/symptoms related to IgM hypergammaglobulinemia and/or LPL infiltration in organs and tissues, especially bone marrow. However, some
patients do not exhibit any clinical symptoms when diagnosis is made.16
Blood hyperviscosity determines hemorheological
changes and is one of the most important characteristics
of WM; however, it is observed in less than 15% of patients upon diagnosis. The large size of the monoclonal
IgM molecule and its high concentration contribute to
increased blood viscosity and vascular resistance, compromising the blood flow to oxygenate tissues.17
The main clinical manifestations associated with the
hyperviscosity syndrome are bleeding (epistaxis, bleeding
gums and gastrointestinal bleeding), ocular changes (papilledema, blindness, blurred vision and retinal changes:
hemorrhage, exudates, dilatation and segmentation of
the retinal veins, venous thrombosis), neurological changes (headache, dizziness, syncope, deafness, ataxia, diplopia, drowsiness and even seizures) and cardiac changes
(heart failure).18
The symptoms of hyperviscosity generally manifest
when the concentration of monoclonal IgM is greater
than 5000 mg/dL or when the serum viscosity reaches 4-5
cP (reference range: 1.4 to 1.8 cP). However, the serum viscosity is not always proportional to the concentration of
IgM and its relationship to symptoms is not linear.16
Type I cryoglobulinemia (monoclonal IgM cryoglobulinemia) is associated with lymphoproliferative diseases such as WM, and is detected in approximately 20% of
patients, while symptomatic in only 5% of cases.19 The
precipitation of monoclonal IgM cryoglobulin is also responsible for some clinical symptoms, such as Raynaud’s
phenomenon, acrocyanosis, purpura and necrosis of body
regions most exposed to the cold. It is also responsible
for the development of distal symmetrical sensorimotor
polyneuropathy or multiple mononeuropathy with axonal degeneration.20,21
Monoclonal IgM can cause platelet dysfunction by
binding to IIIa and Ib glycoproteins on the surface of platelets or due to nonspecific interactions with platelets.9
It may also neutralize the activity of several coagulation
factors (fibrinogen, prothrombin, factors V, VII, VIII, IX,
X, and Von Willebrand factor),9,22 triggering hemostatic
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disorders that are the source of hemorrhagic manifestations.
Monoclonal IgM may exhibit “cold agglutinin” activity, binding to erythrocyte antigens at a temperature lower than physiological temperature, determining the development of chronic cold antibody hemolytic anemia.
This monoclonal immunoglobulin is generally IgM Kappa, which often interacts with I/i antigens on the surface of erythrocytes.23,24 Anemia manifests in less than 10%
of patients and is generally associated with “cold agglutinins” levels above 1:1000.25 The reduction in the temperature of blood flowing through the peripheral blood
vessels favors the binding of IgM “cold agglutinins” to
the surface of erythrocytes.26 This agglutination of erythrocytes in peripheral blood vessels is responsible for
Raynaud’s phenomenon, acrocyanosis and livedo reticularis, which is reversible when large blood circulation resumes.
Type II cryoglobulinemia (mono and polyclonal) is
characterized by the deposition of monoclonal IgM-polyclonal IgG immunocomplexes at the level of blood vessels, with consequent activation of the complement.17 The
main clinical manifestations are vasculitis, purpura, arthralgia, digital necrosis, Raynaud’s phenomenon, peripheral neuropathy in lower limbs, renal impairment (proteinuria, hematuria, nephrotic syndrome), and liver
impairment (hepatomegaly, liver dysfunction).
Around 20% of patients may be experiencing neurological symptoms at the time of diagnosis. The most frequent neurological disorder is a demyelinating distal symmetrical sensorimotor peripheral neuropathy, which
manifests itself slowly and progressively, causing paresthesia and asthenia. About 50% of these patients have
myelin-associated glycoprotein antibodies (MAG anti-antibodies).27 These are generally monoclonal IgM kappa
and are often involved in demyelinating neuropathies.
Monoclonal IgM can also connect nonspecifically to
multiple antigens of the peripheral nerves, triggering axonal impairment.20,28
The biological function of various tissues and/or organs may be altered by the formation and deposition of
monoclonal IgM aggregates, however, the clinical manifestations related to their deposition are not frequent.
The deposition of monoclonal IgM in the basal membrane of the epidermis is associated with bullous skin disease.29 If it occurs at the level of the dermis it contributes to the formation of papular-nodular lesions on the
surface (Macroglobulinemia cutis).30,31 Some patients may
have chronic urticarial erythema, fever and arthralgia (Schnitzler syndrome).32
The deposition of monoclonal IgM in the lamina propria and/or submucosa of the intestine can be associated
with diarrhea, malabsorption and gastrointestinal bleeding.33
Renal failure is not very common; however, monoclonal IgM may accumulate in the renal glomeruli, forming subendothelial deposits that clog glomerular capillaries.34 In this case, there may be moderate but reversible
proteinuria, being the majority of patients asymptomatic.
In primary or light chain amyloidosis (AL amyloidosis), amyloid fibrils may be deposited in the heart, kidneys, liver, lungs and peripheral nerves.20 Cardiac and pulmonary involvement is more frequent in patients with
amyloidosis associated with monoclonal IgM.35,36 AL amyloidosis may be related to the development of symmetrical or asymmetrical sensory-motor polyneuropathy. Patients experience pain, the sensation of “electric shocks”
and thermal sensitivity in the lower limbs. AL amyloidosis may further affect the autonomic nervous system, causing diarrhea, hypotension, impotence and bladder dysfunction.28
The deposition of amyloid A protein (AA amyloidosis) has been documented, although rare,37,38 and may occur in the kidneys and intestines, causing nephrotic syndrome and intestinal malabsorption.39
IgG and IgA hypogammaglobulinemia may occur simultaneously with monoclonal IgM hypergammaglobulinemia, which can contribute to recurrent respiratory tract
infections, but its cause is not well understood and could
be associated with alterations in the development of plasma cells and/or the production of immunoglobulins.40
LPL primarily involves the bone marrow, but the disease can reach the lymph nodes, spleen and liver, among
other organs. Lymphoplasmocytoid/plasmacytic infiltration is responsible for asthenia, fatigue, recurrent fever,
night sweats, weight loss, cytopenia, lymphadenopathy
and organomegaly.17
Fatigue is one of the most common symptoms and
is often associated with normocytic normochromic anemia; around 80% of symptomatic patients have moderate to severe anemia.27 Anemia is not only due to the change in medullary erythropoiesis. Other factors may
contribute to its aggravation, such as gastrointestinal
bleeding, hyperhemolysis, and hyperviscosity itself, which
may cause a decrease in the erythropoietin synthesis.41 It
should be noted that false anemia may be observed in
some patients caused by the high concentration of monoclonal IgM, which contributes to the increase in plasma volume and consequent hemodilution.
Extramedullary infiltration is uncommon, and may
affect the articular and periarticular structures, gastrointestinal tract, lungs, kidneys, skin, eyes and central nervous system.17,27,42
The symptoms of malabsorption, diarrhea, obstipation or bleeding may indicate involvement of the gastrointestinal tract.43-46 Some patients have cellular infiltration
at the pulmonary parenchymal level,47,48 being coughing
the most common symptom, followed by dyspnea and
chest pain. Renal infiltration has also been reported,49 as
well as cutaneous infiltration (maculopapular lesions,
plaques or nodules)7,50 and infiltration of periorbital structures, such as the tear gland and retro-orbital lymphoid
tissue (ocular tremors).51,52
The infiltration of malignant cells in the central
nervous system is responsible for a rare neurological
disorder called Bing-Neel syndrome. Associated symptoms are nystagmus, diplopia, vertigo, memory loss,
mental confusion, motor dysfunction and eventually
coma.17,53
Diagnosis
Table 1 presents the diagnostic criteria for WM. The detection of IgM monoclonal gammopathy is important
for diagnosis, but the serum concentration presents a
great variability between individuals.16
For diagnosis, a bone marrow biopsy is crucial to assess the extent of neoplastic infiltration, the infiltration
pattern and cellular morphology. In WM, medullary infiltrate consists of a monoclonal cellular population of
small B-lymphocytes, in different maturation stages: small
lymphocytes, lymphoplasmocytoid lymphocytes and plasma cells.
The level of differentiation of the infiltrate is variable, ranging from lymphoplasmocytoid (47% of cases),
consisting of small cells and plasmacytoid lymphocytes,
to lymphoplasmacytic (42%), with predominantly small
lymphocytes and plasma cells. The polymorphic state
(11%) is characterized by a broad spectrum of these many
cells.
A high number of mast cells in the medullary infiltrate is frequent, and this finding may help in the differential diagnosis.
LPL may eventually evolve into a more aggressive
form of lymphoma such as as diffuse large B-cell lymphoma.54 This evolution is accompanied by worsening
of clinical symptoms, with development of profound
cytopenia, organomegaly and extramedullary cellular
infiltration.54
In the peripheral blood, plasmacytoid lymphocytes
are sometimes observed, but leukemic symptoms are rarely observed.
Immunophenotyping should be interpreted simultaneously, verifying its consistency with the results of a
bone marrow biopsy. In practice, IgM monoclonal gammopathy associated with the expression of IgM on neoplastic B-lymphocytes with a CD19+, CD20+, CD5-, CD10and CD23- phenotype and intertrabecular pattern of bone
marrow infiltration is sufficient for the diagnosis of MW16
(Table 1). Nevertheless, the phenotypic characteristics are
not always typical and in about 10-20% of cases positivity
for CD5, CD10 or CD23 has been described.17.55,56 Other
common phenotypic features which are not specific but
may be useful for the differential diagnosis with other
lymphoproliferative diseases are the expression of sIgD,
CD22, CD79a, PAX5, Bcl2, FMC7, CD25 and CD27 and
the absence of expression of BCL6, CD103 , CD138, CD56
and CD75. Some of these markers are particularly useful
for studying the bone marrow infiltrate in the bone biopsy
through immunohistochemical and other studies for the
immunophenotypic characterization of B-lymphocytes
by flow cytometry.
Table 1 Clinical and laboratory characteristics of Waldenström’s macroglobulinemia
IgM monoclonal gammopathy of varying concentration
Bone marrow biopsy: ≥10% infiltration by small B-lymphocytes with plasmacytoid/plasmacytic differentiation
Bone marrow biopsy: generally intertrabecular infiltration pattern
Immunophenotyping of B-lymphocytes: CD19+, CD20+, CD5-, CD10-, CD23-, sIgM+ (monoclonal)
Other immunophenotypic characteristics of neoplastic B-lymphocytes: sIgD+, CD22+, CD79a+, PAX5+, Bcl2+, FMC7+, CD25+, CD27+, BCL6-,
CD103-, CD138-, CD56-, CD75Cytogenetic studies: over 50% of cases present deletions (del) 6q
sIgM – Surface immunoglobulin M.
Note: Immunophenotypic variations may occur. Other lymphoproliferative diseases, including marginal zone B-cell lymphoma, chronic lymphocytic leukemia and mantle cell lymphoma should be
excluded.
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The assessment of the clinical status of patients involves several examinations and laboratory tests (Table 2).
When interpreting the results it is important to consider that some parameters could be altered because the
monoclonal IgM may interfere in several measurements
performed in automated analyzers, especially in the evaluation of HDL cholesterol, bilirubin, inorganic phosphate, LDL cholesterol, C-reactive protein, creatinine, glucose, urea, iron and calcium ions.27
Differential diagnosis
It is fundamental to distinguish WM from other disorders that could be clinically confused with this disease.
Differential diagnosis (Table 3) is important for the
exclusion of neoplasms potentially secreting monoclonal IgM and which can also present lymphocytes with
lymphoplasmocytoid differentiation in the bone marrow.
This group includes marginal zone lymphomas,57 chronic lymphocytic leukemia (CD5+, CD23+), mantle cell lymphoma (CD5+, CD23-), follicular lymphoma (CD10+) and
multiple myeloma (CD138+, CD38+, CD56+).17,57
The differentiation between symptomatic WM, asymptomatic WM and IgM monoclonal gammopathy of undetermined significance (MGUS) is important since the
latter patients present risk of progression to symptomatic WM of 1.5%/year.58,59 This differs from asymptomatic
Table 2 Laboratory assessment in patients with clinical suspicion of Waldenström’s macroglobulinemia
Laboratory exam
Clinical justification
Electrophoresis of serum proteins
Detection of monoclonal gammopathy - homogeneous peak, high, narrow
Electrophoresis of urinary proteins (24-hour urine)
base, usually in the area of gamma globulins
Immunofixation of serum and urinary proteins
Characterize the immunoglobulin: heavy chain and light chain
Bone marrow biopsy
Assess the bone marrow infiltration by lymphocytes, the infiltration pattern
and cell morphology
Erythrocyte sedimentation rate
Frequently raised
Cytogenetic studies
Differential diagnosis of other malignancies of B-lymphocytes secreting
monoclonal IgM
Blood test
Evaluation of thrombocytopenia and anemia, which is usually normocytic
- Reticulocyte count
and normochromic
- Concentration of haptoglobin, indirect bilirubin and lactate dehydrogenase
Search autoimmune hemolytic anemia. Useful in patients with Raynaud’s
- Research, identification and quantification of “cold agglutinins”
syndrome, acrocyanosis or limb ulceration
- Direct Coombs Test and title of “cold agglutinins”
Serum viscosity
Determine if the patient has signs and symptoms of hyperviscosity or IgM
concentration >4000 mg/dL
Eye examination - ophthalmoscopy
Justified in the event of changes in vision
Urea, creatinine and transaminases (AST and ALT)
Evaluation of renal and hepatic function
β2-microglobulin
Relevant for prognosis
IgG and IgA
Predisposition to respiratory infections
TTPa, TP, TT
In patients with bleeding diathesis and a tendency to bruise
Detection and semi-quantification of anti-MAG, anti-SGPG, anti- In patients with peripheral neuropathy, such as progressive symmetrical
GM1, anti-sulfatide antibodies
numbness of the limbs, burning sensation and tingling, pain in the feet and
hands
Screening of AL amyloidosis - electrophoresis and immunofixation
In suspected cases of AL amyloidosis
of urinary proteins (24-hour urine)
Confirmation of AL amyloidosis test - abdominal fat aspirate
Electromyography
In patients who have impaired motor function
Computed tomography of the abdomen, trunk and pelvis
Detection of organomegaly (e.g. spleen, liver) and lymphadenopathy
AST, aspartate aminotransferase; ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time; MAG, myelin-associated glycoprotein;
SGPG, sulfate-3-glucuronyl paragloboside; GM1, GM1 ganglioside.
Table 3 Differential diagnosis of Waldenström’s macroglobulinemia (WM) (Adapted from Fonseca and Hayman 200776)
Neoplasm
Immunophenotype
Pattern of marrow infiltration and cell
Cytogenetic abnormalities
morphology
sIgM+(kappa to lambda ratio 5:1), Generally intertrabecular;
Most patients have a normal karyotype;
Waldenström’s
sIgD , CD19 , CD20 , CD22 , Small lymphocytes with plasmacytoid The most frequent cytogenetic alterations are
Macroglobulinemia
CD79a+, PAX5+, Bcl2+, FMC7+, differentiation
+
+
+
+
6q21-23 deletions
CD5 +/-, Bcl6 - , CD10 - , CD23 - ,
CD25+ CD27+, CD103-, CD138-,
CD56Multiple Myeloma
cIg+, sIg-, CD19-, CD20-, PAX5-, Nodular, diffuse, interstitial;
CD38+, CD79a+, CD138+, CD56+
t(11;14) (q13;q32)
Plasma cells with different degrees of
maturation
sIg (weak), CD43 (weak), Nodular, interstitial, diffuse or mix of
Del 13q14 (50% of cases);
B-cell chronic
CD20+ (weak), CD19+, CD23+, all three;
Del 11q (20% of cases);
lymphocytic
CD5+, CD23+, CD10-, CD79b/ Small lymphocytes with dense nucleus, Trisomy of chromosome 12 (20% of cases);
leukemia
CD22-, FMC7-, Cyclin D1-
+
+
aggregated chromatin, no visible nucleoli
Del 17p;
and reduced cytoplasm
Presence of ZAP-70+ (Tyrosine Kinase of 70
Kda associated to the zeta chain of the T
lymphocyte receptor complex)
Mantle cell
sIgM ,sIgD , lambda light chain
lymphoma
restriction, CD19+, CD20+, CD5+, Lymphocytes are small or medium in
+
+/-
Variable infiltration pattern.
t(11;14) (q13;q32)
CD43 + , FMC-7 + , Cyclin D1 + , size with irregular nucleus
CD10-, BCL-6-, CD23Follicular
sIg +, CD10 +, CD19 +, CD20+, Paratrabecular infiltration;
lymphoma
CD21 +, CD22 +, CD79a +, Bcl - Centrocytes (small cells with “cleaved”
t(14;18)(q32;q21) (70-95% of cases).
2+,Bcl-6+, CD43-, CD5-, CD23-, nuclei and reduced cytoplasm) and
CD43-
centroblasts (large cells with round or
oval nuclei, vesicular chromatin, and
low basophilic cytoplasm)
Extranodal
sIgM + (generally), light chain
Variable
Trisomy 3 (60% of cases);
marginal zone
restriction (generally), CD19+,
t(11;18) (q21;q21) (25%-50% of cases);
lymphoma, MALT
CD20+, CD21+, CD35+, CD22+,
t(1;14) (p22;q32);
CD79+, CD43+/-, CD5-, CD10-,
t(11;18) (q21;q22);
CD23-, CD11c+ (weak)/CD11c-
t(14;18) (q32;q21);
t(3;14) (p13;q32)
Nodal marginal
Most lymphomas have a similar
zone lymphoma
immunophenotype to MALT
Variable
Trisomy 3;
t(11;18) (q21;q21)
lymphoma, others have a similar
immunophenotype to splenic
marginal zone lymphomas
Splenic marginal
sIgM+, IgD+(generally), CD19+, Nodular, interstitial
Chromosomal gains: 3q (30-40% of cases), 5q
zone lymphoma
CD20 , CD22 , Bcl-2 , CD79a ,
(28%), 12q (24%), 20q (24%), 9q (21%), 4q
+
+
+
+
CD5 -, CD23 -, CD10 -, CD43 -,
(17%);
CD25-, CD103-, Cyclin D1-
Trisomy 3 (17%);
Del 7q;
Del 6q and Del 17p – Genetic alterations
associated with clinical progression of the
disease
cIg – cytoplasmic immunoglobulin, sIg, surface immunoglobulin; MALT, mucosa-associated lymphoid tissue.
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WM due to the lower concentration of monoclonal IgM
(< 3 g/dL) and absence of bone marrow infiltration (<10%).
The risk of progression from asymptomatic to symptomatic WM is 6%/year, and only 55% of these patients will
show progression within 5 years3.
Prognosis of symptomatic WM
The International Prognostic Staging System for Waldenström Macroglobulinemia adopts five variables that
correlate with poor survival of patients under treatment:
age> 65 years, β2-microglobulin concentration >3 mg/L,
platelets count ≤100x109/L, monoclonal IgM concentration > 7000 mg/dL, and hemoglobin concentration ≤11.5g/
dL.60 The absence or presence of one or more prognostic
factors categorizes the patient into 3 risk levels: low (0 -1
risk factor, excluding age), intermediate (2 risk factors
and age > 65 years) or high (more than 3 risk factors).60
Based on the degree of risk, it is possible to estimate
the average/overall survival. In patients at low risk, the
average survival time is 12 years, and treatment should
involve low toxicity, preserving quality of life. The use of
this system in symptomatic patients that are candidates
for treatment enables tailoring treatment to the patient,
taking into account the estimated average survival.
In a recent study, high concentrations of lactate dehydrogenase (> 250 IU/L) were also seen as a poor prognosis factor, especially in high risk patients.61
Treatment
Clinical decision to prescribe therapy takes into account
different factors such as patient age, clinical manifestations, prognostic factors, quality of life and patient survival potential, the risk/benefit and cost/benefit of treatment, effectiveness and side effects.
The treatment of asymptomatic patients does not improve their quality of life and survival;3 biannual clinical
observation is the recommended option in these cases if
hematologic function is preserved.3 There is a study that
suggests bimonthly/quarterly follow-ups during the first
year after diagnosis and, if remaining stable, monitoring
should be quarterly/half-yearly in the following years.62
Patients with WM are candidates for treatment if they
have clinical evidence of aggressive disease progression
or if they have had clinical and laboratory manifestations
associated with WM, such as lymphadenopathy or splenomegaly, symptoms of hyperviscosity, severe peripheral
neuropathy, AL amyloidosis (resulting in tissue deposition of light immunoglobulin chains), cryoglobulinemia,
autoimmune hemolytic anemia, hemoglobin concentration <10 g/dL and/or platelet count <100x109/L.63
In fact, the choice of treatment is a critical option and
should not be taken so as to limit future options, since
all patients will inevitably present relapses after initial
treatment, requiring treatment.3 Age, the presence of cytopenia, the need to control the disease and the possibility of autologous stem cell transplantation should be
considered in the approach to treatment.63
First-line therapy includes alkylating agents, purine
analogs and monoclonal anti-CD20 antibodies.63 Treatment with alkylating agents may cause cytopenias and
myelosuppression, and should be avoided in patients that
are candidates for autologous transplantation.63,64 Purine analogs may be responsible for the development of
myelodysplasia and acute myeloid leukemia.63.65
The Mayo Clinic has developed a therapeutic approach
adapted to the clinical characteristics of the patient.3 Most
symptomatic patients are treated with Rituximab as monotherapy or combined with chemotherapy. Monotherapy is recommended in symptomatic patients with moderate hematological impairment, in patients with
neuropathy associated with the IgM autoantibody, and
in cases of hemolytic anemia resistant to corticosteroids.3
Rituximab is an IgG1 anti-CD20 monoclonal antibody. The connection to the CD20 receptor on B-lymphocytes activates the complement cascade, leading to
the formation of the membrane attack complex that induces cell lysis.66 This antibody also activates natural killer cells by binding to receptors for the Fc fragment of
IgG (FcγR), leading to cell lysis. The fragments of complement component C3, together with rituximab, are recognized by the membrane of macrophages, binding to
receptors for complement component C3 and FcγR receptors, respectively, and activating phagocytosis.66,67 The
genetic polymorphism of FcγR receptors may condition
the treatment response,68 and a correlation has been observed between polymorphisms at position 158 of the
FcγRIIIa (CD16) receptor and the response to rituximab.
At the start of rituximab treatment, some patients
have a paradoxical and often transient increase in serum
concentrations of IgM (IgM flare), which can persist for
up to 4 months and is not indicative of treatment failure.69,70 The underlying mechanism remains unclear, but
two hypotheses have been proposed - release of intracellular IgM resulting from rituximab-mediated cell death
and cell signaling mediated by binding to CD20.71
In patients requiring urgent control of the disease, plasmapheresis is indicated if they have clinical manifestations
of moderate to severe hyperviscosity, cryoglobulinemia and
cytopenias caused by the action of the monoclonal IgM
autoantibody.62,3 Usually 2 to 3 plasmapheresis sessions
are necessary to reduce the concentration of IgM from 30
to 60%. The sessions should be repeated daily until symptoms subside or until normalization of serum viscosity.
Subsequent treatment should be started quickly, as the
concentration of IgM will return to its initial level after 4
to 5 weeks.62 These patients should be treated with the dexamethasone, rituximab and cyclophosphamide (DRC)
combination regimen. The main reasons for choosing this
regimen in these patients are the good treatment tolerance, reduced myelosuppression and the lack of toxicity for
stem cells.3,65
In patients with relapses or who are refractory to therapy, the choice of treatment depends on the first-line
treatment already utilized, the quality/duration of the
response and other variables, such as age, tolerance to initial treatment, and also the possibility of the patient being a candidate for stem cell transplantation.63
The reuse of the first-line treatment is recommended
if the response to initial treatment was maintained without maintenance for at least 12 months. Otherwise,
another first-line agent or combination therapy should
be used.63
In patients with short-term remission or resistance
to initial treatment, therapy with a drug of different pharmacological class as monotherapy or combined is recommended. In association therapy, a regime using rituximab,
fludarabine and cyclophosphamide is highlighted; however, the latter should be avoided in younger patients and
candidates for autologous stem cell transplantation.63
The use of bortezomib (proteasome inhibitor) has proven promising, as well as alemtuzumab (anti-CD52 monoclonal antibody) datalidomida, enzastaurin (protein kinase C inhibitor), everolimus (inhibitor of mammalian target
of rapamycin - mTOR) and perifosine (Akt inhibitor).62,64,72
Histone deacetylase inhibitors treatment agents, such as
panobinostat (LBH589), new proteasome inhibitors, such
as carfilzomib, human anti-CD20 monoclonal antibody,
such as ofatumumab, and alkylating agents, such as bendamustine, also seem to be promising agents.72
Transplantation of hematopoietic stem cells is indicated in younger patients with multiple recurrences or who
have been refractory to previous treatments.62 Autologous
transplantation is associated with improved survival and
long periods without disease progression, and should be
considered in all candidate patients presenting relapse.3
The concentration of monoclonal IgM is one of the
parameters most commonly used among the criteria for
assessing response to treatment. However, this biomarker is not always reliable, since its concentration can be
affected by the treatment itself.62
Taking into account the criteria for treatment response, complete response is observed when IgM serum
levels normalize with complete disappearance of IgM monoclonal protein (by immunofixation), histological evaluation of the bone marrow shows no evidence of disease, and all symptoms, lymphadenopathy and/or
organomegaly are resolved. Partial response is considered in a scenario of ≥ 50% decrease in the monoclonal IgM
serum concentration, decreased lymphadenopathy/organomegaly and absence of new symptoms and/or signs of
active disease on electrophoresis of serum proteins compared to the baseline values. A minimal response is observed when the reduction in electrophoresis of monoclonal IgM is <50 but ≥ 25%, and no new symptoms and/
or signs of active disease are observed. The stable disease
corresponds to cases in which the value of monoclonal
IgM relative to baseline undergoes a reduction of <25%
and increases <25%, with no progression of lymphadenopathy/organomegaly and cytopenias, and no significant
clinical signs or symptoms. The disease is considered progressive when there is an increase in the detectable amount
of protein electrophoresis and monoclonal IgM serum
levels ≥ 25% (confirmed by a second assessment) or progression of complications resulting from the disease or
symptoms attributed to WM.73
The concentration of sCD27 and assessment of the
amount of monoclonal free light chains have been presented as potential biomarkers for laboratory monitoring of therapy.74,75 The investigation of alternative biomarkers is essential for a more reliable and less invasive
clinical evaluation.
Resumo
Macroglobulinemia de Waldenström – uma revisão.
A macroglobulinemia de Waldenström (MW) é uma doença linfoproliferativa dos linfócitos B, caracterizada por um
linfoma linfoplasmocítico na medula óssea e por hipergamaglobulinemia monoclonal de tipo IgM. Foi descrita pela
primeira vez em 1944, por Jan Gösta Waldenström, que
descreveu dois doentes com hemorragia oronasal, adenopatias, anemia, trombocitopenia, velocidade de sedimentação eritrocitária e viscosidade sérica elevadas, radiografia óssea normal e medula óssea infiltrada por células
linfoides.
A MW é uma doença rara com um percurso clínico normalmente indolente, atingindo principalmente os indivíduos
com idades entre 63 e 68 anos. A maioria dos doentes apresenta sintomas e manifestações clínicas relacionadas com a
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Coimbra S et al.
hiperviscosidade, resultante da gamopatia monoclonal IgM
e/ou com as citopenias, resultantes da infiltração medular
pelo linfoma. O diagnóstico diferencial com outros linfomas é essencial para a avaliação do prognóstico e a abordagem terapêutica.
O tratamento dos doentes com MW assintomática não
melhora a qualidade de vida do doente nem aumenta a
sua sobrevivência, recomendando-se o acompanhamento clínico. Para o tratamento dos doentes sintomáticos,
são usados agentes alquilantes, análogos das purinas e
anticorpos monoclonais anti-CD20. No entanto, a doença é incurável e a resposta à terapêutica nem sempre é favorável. Estudos relativamente recentes mostram resultados promissores com o bortezomibe, um inibidor dos
proteossomas, e alguns doentes respondem à talidomida. Nos doentes com recidivas ou refratários à terapêutica, pode-se indicar o transplante autólogo.
O objetivo deste trabalho é descrever, de forma detalhada, o conhecimento atual sobre a fisiopatologia da MW,
as principais manifestações clínicas, o diagnóstico, o prognóstico e o tratamento.
Palavras-chave: macroglobulinemia de Waldenström;
hipergamaglobulinemia; IgM; linfócitos B; prognóstico.
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Diagnosis and management of Waldenstrom macroglobulinemia: Mayo
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